Substituted aminothiazolone indazoles as estrogen related receptor-alpha modulators

ABSTRACT

The present invention relates to compounds of Formula (I), 
                         
methods for preparing these compounds, compositions, intermediates and derivatives thereof and for treating a condition including but not limited to ankylosing spondylitis, artherosclerosis, arthritis (such as rheumatoid arthritis, infectious arthritis, childhood arthritis, psoriatic arthritis, reactive arthritis), bone-related diseases (including those related to bone formation), breast cancer (including those unresponsive to anti-estrogen therapy), cardiovascular disorders, cartilage-related disease (such as cartilage injury/loss, cartilage degeneration, and those related to cartilage formation), chondrodysplasia, chondrosarcoma, chronic back injury, chronic bronchitis, chronic inflammatory airway disease, chronic obstructive pulmonary disease, diabetes, disorders of energy homeostasis, gout, pseudogout, lipid disorders, metabolic syndrome, multiple myeloma, obesity, osteoarthritis, osteogenesis imperfecta, osteolytic bone metastasis, osteomalacia, osteoporosis, Paget&#39;s disease, periodontal disease, polymyalgia rheumatica, Reiter&#39;s syndrome, repetitive stress injury, hyperglycemia, elevated blood glucose level, and insulin resistance.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application61/287,740, filed on Dec. 18, 2009, which is incorporated by referenceherein in its entirety.

FIELD OF THE INVENTION

The present invention relates to certain novel compounds, methods forpreparing compounds, compositions, intermediates and derivatives thereofand for treating conditions such as cancer, arthritis, inflammatoryairway disease, and metabolic disorders. More particularly, thecompounds of the present invention are Estrogen Related Receptor alpha(ERR-α) modulators useful for treating, ameliorating, preventing orinhibiting the progression of disease states, disorders, and conditionsmediated by ERR-α activity.

BACKGROUND OF THE INVENTION

Nuclear receptors are members of a superfamily of transcription factors.The members of this family share structural similarities and regulate adiverse set of biological effects (Olefsky, J. M. J. Biol. Chem. 2001,276(40), 36863-36864). Ligands activate or repress these transcriptionfactors that control genes involved in metabolism, differentiation andreproduction (Laudet, V. and H. Gronmeyer. The Nuclear ReceptorFactbooks. 2002, San Diego: Academic Press). Presently, the human genomeproject has identified about 48 members for this family and cognateligands have been identified for about 28 of them (Giguere, V. EndocrineRev. 1999, 20(5), 689-725). This protein family is composed of modularstructural domains that can be interchanged within the members of thefamily without loss of function. A typical nuclear receptor contains ahypervariable N-terminus, a conserved DNA binding domain (DBD), a hingeregion, and a conserved ligand-binding domain (LBD). The function of theDBD is targeting of the receptor to specific DNA sequences (NuclearHormone Receptor (NHR) response elements or NREs), and the function ofthe LBD is recognition of its cognate ligand. Within the sequence of thenuclear receptor there are regions involved in transcriptionalactivation. The Activation Function 1 (AF-1) domain is situated at theN-terminus and constitutively activates transcription (Rochette-Egly, C.et al. Cell 1997, 90, 97-107; Rochette-Egly, C. et al. Mol. Endocrinol.1992, 6, 2197-2209), while the Activation Function 2 (AF-2) domain isembedded within the LBD and its transcriptional activation is liganddependent (Wurtz, J. M. et al. Nat. Struct. Biol. 1996, 3, 87-94).Nuclear receptors can exist as monomers, homodimers or heterodimers andbind to direct or inverted nucleotide repeats (Laudet and Gronmeyer,2002; Aranda, A. and A. Pascual. Physiol. Rev. 2001, 81(3), 1269-1304).

The members of this family exist either in an activated or repressedbasal biological state. The basic mechanism of gene activation involvesligand dependent exchange of co-regulatory proteins. These co-regulatoryproteins are referred to as co-activators or co-repressors (McKenna, L.J. et al. Endocrine Rev. 1999, 20, 321-344). A nuclear receptor in therepressed state is bound to its DNA response element and is associatedwith co-repressor proteins that recruit histone de-acetylases (HDACs)(Jones, P. L. and Y. B. Shi. Curr. Top. Microbiol. Immunol. 2003, 274,237-268). In the presence of an agonist there is an exchange ofco-repressors with co-activators that in turn recruit transcriptionfactors that assemble into an ATP dependent chromatin-remodelingcomplex. Histones are hyper-acetylated, causing the nucleosome tounfold, and repression is alleviated. The AF-2 domain acts as the liganddependent molecular switch for the exchange of co-regulatory proteins.In the presence of an agonist the AF-2 domain undergoes a conformationaltransition and presents a surface on the LBD for interaction withco-activator proteins. In the absence of an agonist or in the presenceof an antagonist the AF-2 domain presents a surface that promotesinteractions with co-repressor proteins. The interaction surfaces on theLBD for both co-activators, and co-repressors overlap and provide aconserved molecular mechanism for gene activation or repression that isshared by the members of this family of transcription factors (Xu, H. E.et al. Nature 2002, 415 (6873), 813-817).

Natural ligands that modulate the biological activity of nuclearreceptors have been identified for only approximately one half of knownnuclear receptors. Receptors for which no natural ligand has beenidentified are termed “orphan receptors.” The discovery of ligands orcompounds that interact with an orphan receptor will accelerate theunderstanding of the role of the nuclear receptors in physiology anddisease and facilitate the pursuit of new therapeutic approachesEstrogen related receptors (ERRs) constitutes a sub-class of thesereceptors where no ligand has been identified.

ERR-α (also known as ERR-1), an orphan receptor, is the first of thethree identified members of the estrogen receptor related subfamily oforphan nuclear receptors (ERR-α, β, γ). The ERR subfamily is closelyrelated to the estrogen receptors (ER-α and ER-β). ERR-α and ERR-β werefirst isolated by a low stringency hybridization screen (Giguere, V. etal. Nature 1988, 331, 91-94) followed later with the discovery of ERR-γ(Hong, H. et al. J. Biol. Chem. 1999, 274, 22618-22626). The ERRs andERs share sequence similarity with the highest homology observed intheir DBDs, approximately 60%, and all interact with the classical DNAestrogen response element. Recent biochemical evidence suggested thatthe ERRs and ERs share target genes, including pS2, lactoferin,aromatase and osteopontin, and share co-regulator proteins (Giguere, V.Trends in Endocrinol. Metab. 2002, 13, 220-225; Vanacker, J. M. et al.EMBO J. 1999, 18, 4270-4279; Kraus, R. J. et al. J. Biol. Chem. 2002,272, 24286-24834; Hong et al., 1999; Zhang, Z. and C. T. Teng. J. Biol.Chem. 2000, 275, 20387-20846). Therefore, one of the main functions ofERR is to regulate the response of estrogen responsive genes. The effectof the steroid hormone estrogen is primarily mediated in the breast,bone and endometrium. Thus, the identification of compounds that willinteract with ERRs should provide a benefit for the treatment of bonerelated disease, breast cancer and reproduction.

ERR-α is shown to be present both in normal and breast cancer tissue(Ariazi, E. A. et al. Cancer Res. 2002, 62, 6510-6518). It has beenreported that the main function of ERR-α in normal breast tissue is thatof a repressor for estrogen responsive genes. In breast cancers or celllines that are non-estrogen responsive (ER-α negative), ERR-α has beenreported to be in an activated state (Ariazi et al., 2002). Therefore,compounds that will interact with ERR-α may be useful agents for thetreatment of breast cancer that is ER-α negative and non-responsive toclassical anti-estrogenic therapy, or may be used as an adjunct agentfor anti-estrogen responsive breast cancers. These agents may act asantagonists by reducing the biological activity of ERR-α in theseparticular tissues.

Many post-menopausal women experience osteoporosis, a condition that isa result of the reduction of estrogen production. Reduction of estrogenlevels results in an increase of bone loss (Turner, R. T. et al.Endocrine Rev. 1994, 15(3), 275-300). An anabolic effect on bonedevelopment has been observed on the administration of estrogens topostmenopausal patients with osteoporosis (Pacifici, R. J. Bone Miner.Res. 1996, 11(8), 1043-1051) but the molecular mechanism is unknownsince ER-a and ER-b knock-out animals have minor skeletal defects, wherethe action of estrogens is typically mediated (Korach, K. S. Science1994, 266, 1524-1527; Windahl, S. H. et al. J. Clin. Invest. 1999,104(7), 895-901). Expression of ERR-α in bone is regulated by estrogen(Bonnelye, E. et al. Mol. Endocrin. 1997, 11, 905-916; Bonnelye, E. etal. J. Cell Biol. 2001, 153, 971-984). ERR-α is maintained throughoutosteoblast differentiation stages. Over-expression of ERR-α in ratcalvaria osteoblasts, an accepted model of bone differentiation, resultsin an increase of bone nodule formation, while treatment of rat calvariaosteoblasts with ERR-α antisense results in a decrease of bone noduleformation. ERR-α also regulates osteopontin, a protein believed to beinvolved in bone matrix formation. Therefore compounds that willmodulate ERR-α by increasing its activity can have an anabolic effectfor the regeneration of bone density and provide a benefit over currentapproaches that prevent bone loss, but have no anabolic effect. Suchcompounds can enhance the activity of the receptor by two possiblemechanisms: i) enhancing the association of the receptor with proteinsthat enhance its activity or improve the stability of the receptor; andii) increasing the intracellular concentrations of the receptor andconsequently increasing its activity. Conversely, with respect to bonediseases that are a result of abnormal bone growth, compounds that willinteract with ERR-α and decrease its biological activity may provide abenefit for the treatment of these diseases by retarding bone growth.Antagonism of the association of the receptor with co-activator proteinsdecreases the activity of the receptor.

ERR-α is also present in cardiac, adipose, and muscle tissue and forms atranscriptional active complex with the PGC-1 co-activator family,co-activators implicated with energy homeostasis, mitochondriabiogenesis, hepatic gluconeogenesis and in the regulation of genesinvolved in fatty acid beta-oxidation (Kamei, Y. et al. Proc. Natl.Acad. Sci. USA 2003, 100(21), 12378-12383). ERR-α regulates theexpression of the medium chain acyl-CoA dehydrogenase promoter (MCAD).Medium chain acyl-CoA dehydrogenase is a gene involved in the initialreaction in fatty acid beta-oxidation. It is believed that in theadipose tissue ERR-α regulates energy expenditure through the regulationof MCAD (Sladek, R. et al. Mol. Cell. Biol. 1997, 17, 5400-5409; Vega,R. B. and D. P. Kelly. J. Biol. Chem. 1997, 272, 31693-31699). Inantisense experiments in rat calvaria osteoblasts, in addition to theinhibition of bone nodule formation, there was an increase in adipocytedifferentiation markers including aP2 and PPAR-γ (Bonnelye, E. et al.Endocrinology 2002, 143, 3658-3670). Recently an ERR-α knockout modelhas been described that exhibited reduced fat mass relative to the wildtype and DNA chip analysis data indicated alteration of the expressionlevels of genes involved in adipogenesis and energy metabolism (Luo, J.et al. Mol. Cell. Biol. 2003, 23(22), 7947-7956). More recently it hasbeen shown that ERR-α regulates the expression of endothelial nitricoxide synthase, a gene that has a protective mechanism againstarteriosclerosis (Sumi, D. and L. J. Ignarro. Proc Natl. Acad. Sci.2003, 100, 14451-14456). The biochemical evidence supports theinvolvement of ERR-α in metabolic homeostasis and differentiation ofcells into adipocytes. Therefore, compounds interacting with ERR-α canaffect energy homeostasis and may therefore provide a benefit for thetreatment of obesity and metabolic syndrome related disease indications,including arteriosclerosis and diabetes (Grundy, S. M. et al.Circulation 2004, 109(3), 433-438).

There is a continuing need for new ERR-α modulators. There is also aneed for ERR-α modulators useful for the treatment of conditionsincluding but not limited to ankylosing spondylitis, artherosclerosis,arthritis (such as rheumatoid arthritis, infectious arthritis, childhoodarthritis, psoriatic arthritis, reactive arthritis), bone-relateddiseases (including those related to bone formation), breast cancer(including those unresponsive to anti-estrogen therapy), cardiovasculardisorders, cartilage-related disease (such as cartilage injury/loss,cartilage degeneration, and those related to cartilage formation),chondrodysplasia, chondrosarcoma, chronic back injury, chronicbronchitis, chronic inflammatory airway disease, chronic obstructivepulmonary disease, diabetes, disorders of energy homeostasis, gout,pseudogout, lipid disorders, metabolic syndrome, multiple myeloma,obesity, osteoarthritis, osteogenesis imperfecta, osteolytic bonemetastasis, osteomalacia, osteoporosis, Paget's disease, periodontaldisease, polymyalgia rheumatica, Reiter's syndrome, repetitive stressinjury, hyperglycemia, elevated blood glucose level, and insulinresistance.

SUMMARY OF THE INVENTION

In its many embodiments, the present invention provides novel compoundsuseful as, for example, ERR-α modulators, methods of preparing suchcompounds, pharmaceutical compositions comprising one or more suchcompounds, methods of preparing pharmaceutical compositions comprisingone or more such compounds, and methods of treatment, prevention,inhibition or amelioration of one or more diseases associated with ERR-αusing such compounds or pharmaceutical compositions.

One aspect of the present invention features a compound of Formula (I)

wherein

X is —CH— or N;

R₁ is C₁₋₃alkyl, halo, cycloalkyl, or —C(O)—C₁₋₄alkyl; wherein saidC₁₋₃alkyl may be substituted with halo;

R₂ is —H, halo, cyano, C₂₋₄alkenyl, C₁₋₄alkoxy, hydroxyl, cycloalkyl,—C(O)O—C₁₋₄alkyl, —C(O)NH₂, —OS(O₂)—C₁₋₄alkyl, heterocyclyl, heteroaryl,or —S(O₂)—C₁₋₄alkyl; wherein said C₁₋₃alkyl may be substituted with haloor hydroxyl,

R₃ is —H, halo, cyano, or C₁₋₃alkyl; and

is a 4 to 9 membered heterocyclyl bonded to the rest of the moleculethrough a ring nitrogen atom and optionally containing 1-2 heteroatomsin addition to said ring nitrogen atom, wherein the optional 1-2additional heteroatoms are independently selected from the groupconsisting of N, O and S;

wherein said 4 to 9 membered heterocyclyl may be substituted withC₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, halo, oxo, cyano, hydroxyl, —OR⁵,—O—C₁₋₄alkyl-C(O)OR⁵, cycloalkyl, heteroaryl, heterocyclyl, —C(O)OR⁵,—C(O)N(R⁵)(R⁶), —C(O)N(R⁵)(OR⁶), —C(O)R⁵, —C(O)—C₁₋₄alkyl-N(R⁵)(R⁶),—C(O)—C₁₋₄-alkyl-O—C₁₋₄alkyl, —C(O)N(R⁵)—S(O)₂(R⁶), —C(O)N(R⁵)—OR⁶,—C(O)N(R⁵)S(O)₂N(R⁵)(R⁶), -alkyl, —C(O)N(R⁵)—C₁₋₄alkyl-C(O)OR⁶,—N(R⁵)(R⁶), —N(R⁵)—C₁₋₄alkyl—OR⁶, —N(R⁵)C(O)R⁶, —N(R⁵)C(O)OR⁶,—N(R⁵)S(O)₂R⁶, —N(R⁵)C(O)—NH(R⁶), —N(R⁵)—C₁₋₄alkyl-C(O)—NH(R⁶), —SR⁵,—S(O)₂R⁵, or —S(O)₂—N(R⁵)(R⁶);

wherein said C₁₋₄alkyl may be substituted with —OH, —O—C₁₋₄alkyl,—C(O)OR⁵, —C(O)N(R⁵)(R⁶), —N(R⁵)(R⁶), —N(R⁵)C(O)OR⁶, heterocyclyl,heteroaryl, cycloalkyl, or halo;

wherein said heteroaryl may be substituted with C₁₋₄alkyl, halo, cyano,—CF₃, alkoxy or hydroxyl;

wherein said heterocyclyl may be substituted with C₁₋₄alkyl, oxo, halo,amino, alkoxy, or hydroxyl;

wherein said C₂₋₄alkenyl and said C₂₋₄alkynyl may be independentlysubstituted with oxo, heterocyclyl, hydroxyl, or halo;

wherein R⁵ and R⁶ are each independently H, C₁₋₄alkyl, cycloalkyl, orheterocyclyl, wherein said C₁₋₄alkyl may be substituted with halo orhydroxyl; or alternatively R⁵ and R⁶ are linked together to form a 5 to7 membered ring;

or an optical isomer, enantiomer, diastereomer, cis-trans isomer,racemate, or pharmaceutically acceptable salt thereof.

Another aspect of the present invention features a pharmaceuticalcomposition comprising at least one compound of Formula (I) and at leastone pharmaceutically acceptable carrier.

The present invention also features a method of treating a subjectsuffering from or diagnosed with a disease, disorder, or conditionmediated by ERR-α activity, comprising administering to the subject atherapeutically effective amount of at least one compound of Formula(I). Such disease, disorder, or condition can include, but is notlimited to ankylosing spondylitis, artherosclerosis, arthritis (such asrheumatoid arthritis, infectious arthritis, childhood arthritis,psoriatic arthritis, reactive arthritis), bone-related diseases(including those related to bone formation), breast cancer (includingthose unresponsive to anti-estrogen therapy), cardiovascular disorders,cartilage-related disease (such as cartilage injury/loss, cartilagedegeneration, and those related to cartilage formation),chondrodysplasia, chondrosarcoma, chronic back injury, chronicbronchitis, chronic inflammatory airway disease, chronic obstructivepulmonary disease, diabetes, disorders of energy homeostasis, gout,pseudogout, lipid disorders, metabolic syndrome, multiple myeloma,obesity, osteoarthritis, osteogenesis imperfecta, osteolytic bonemetastasis, osteomalacia, osteoporosis, Paget's disease, periodontaldisease, polymyalgia rheumatica, Reiter's syndrome, repetitive stressinjury, hyperglycemia, elevated blood glucose level, and insulinresistance. The therapeutically effective amount of the compound ofFormula (I) can be from about 0.1 mg/day to about 5000 mg/day.

The present invention further features a process for making apharmaceutical composition comprising admixing any of the compoundsaccording to Formula (I) and a pharmaceutically acceptable carrier.

Additional embodiments and advantages of the invention will becomeapparent from the detailed discussion, schemes, examples, and claimsbelow.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to novel ERR-α modulators and compositionsthereof for the treatment, amelioration, prevention or inhibition ofnumerous conditions, including but not limited to cancer, arthritis,inflammatory airway disease, bone-related diseases, metabolic disorders,and associated symptoms or complications thereof.

One aspect of the present invention features a compound of Formula (I)

wherein

X is —CH— or N;

R₁ is C₁₋₃alkyl, halo, cycloalkyl, and —C(O)—C₁₋₄alkyl; wherein theC₁₋₃alkyl may be substituted with halo;

R₂ is —H, halo, cyano, C₁₋₃alkyl, C₂₋₃alkenyl, C₁₋₄alkoxy, hydroxyl,cycloalkyl, —C(O)O—C₁₋₄alkyl, —C(O)NH₂, —OS(O₂)—C₁₋₄alkyl,—O—C₁₋₄alkyl—O—C₁₋₄alkyl, heterocyclyl, heteroaryl, or —S(O₂)—C₁₋₄alkyl;

wherein the C₁₋₃alkyl may be substituted with halo or hydroxyl;

R₃ is —H, halo, cyano, or C₁₋₃alkyl; and

is a 4 to 9 membered heterocyclyl bonded to the rest of the moleculethrough a ring nitrogen atom and optionally containing 1-2 heteroatomsin addition to said ring nitrogen atom, wherein the optional 1-2additional heteroatoms are independently selected from the groupconsisting of N, O and S;

wherein said 4 to 9 membered heterocyclyl may be substituted withC₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, halo, oxo, cyano, hydroxyl, —OR⁵,—O—C₁₋₄alkyl-C(O)OR⁵, cycloalkyl, heteroaryl, heterocyclyl, —C(O)OR⁵,—C(O)N(R⁵)(R⁶), —C(O)N(R⁵)(R⁶), —C(O)R⁵, —C(O)—C₁₋₄alkyl-N(R⁵)(R⁶),—C(O)—C₁₋₄alkyl—O—C₁₋₄alkyl, —C(O)N(R⁵)—S(O)₂(R⁶), —C(O)N(R⁵)—OR⁶,—C(O)N(R⁵)S(O)₂N(R⁵)(R⁶), —C(O)N(R⁵)—C₁₋₄alkyl-C(O)OR⁶, —N(R⁵)(R⁶),—N(R⁵)—C₁₋₄alkyl—OR⁶, —N(R⁵)C(O)R⁶, —N(R⁵)C(O)OR⁶, —N(R⁵)S(O)₂R⁶,—N(R⁵)C(O)—NH(R⁶), —N(R⁵)—C₁₋₄alkyl-C(O)—NH(R⁶), —SR⁵, —S(O)₂R⁵, or—S(O)₂—N(R⁵)(R⁶);

wherein said —C₁₋₄alkyl may be substituted with —OH, —O—C₁₋₄alkyl,—C(O)OR⁵, —C(O)N(R⁵)(R⁶), —N(R⁵)(R⁶), —N(R⁵)C(O)OR⁶, heterocyclyl,heteroaryl, cycloalkyl, or halo;

wherein said heteroaryl may be substituted with C₁₋₄alkyl, halo, cyano,—CF₃, alkoxy or hydroxyl;

wherein said heterocyclyl may be substituted with C₁₋₄alkyl, oxo, halo,amino, alkoxy, or hydroxyl;

wherein said C₂₋₄alkenyl and said C₂₋₄alkynyl may be independentlysubstituted with oxo, heterocyclyl, hydroxyl, or halo;

wherein R⁵ and R⁶ are each independently —H, C₁₋₄alkyl, cycloalkyl, orheterocyclyl, wherein said C₁₋₄alkyl may be substituted with halo orhydroxyl; or

alternatively R⁵ and R⁶ are linked together to form a 5 to 7 memberedring;

or an optical isomer, enantiomer, diastereomer, cis-trans isomer,racemate or pharmaceutically acceptable salt thereof.

In particular, the present invention includes a cis-trans isomer of thecompound of Formula (I), which has the following structure, wherein X,R₁, R₂, R₃ and

are as described above:

Particularly, X is N. More particularly, X is —CH—.

Particularly, R₁ is —C(O)—C₁₋₂alkyl, —Cl, —Br, —I, C₁₋₃alkyl, orC₃₋₅cycloalkyl; wherein the C₁₋₃alkyl may be substituted with halo. Moreparticularly, R₁ is —C(O)—CH₃, —Cl, —Br, —I, —CF₃, or cyclopropyl.

Particularly, R₂ is —F, —Cl, —Br, cyclopropyl, C₁₋₃alkyl, C₁₋₂alkoxy, orhydroxyl; wherein the C₁₋₃alkyl may be substituted with halo orhydroxyl. More particularly, R₂ is —CF₃, hydroxyl, —OCH₃, or —Cl. Moreparticularly, R₂ is —CF₃, —OCH₃, or —Cl. Even more particularly, R₂ is—CF₃, or —Cl. Particularly, R₂ is —CF₃.

Particularly, R₃ is —H, halo, or cyano. More particularly, R₃ is —H.

Particularly,

is an N-containing heterocyclyl.

Particularly,

is a 4 to 9 membered heterocyclyl bonded to the rest of the moleculethrough a ring nitrogen atom and containing 0-2 heteroatoms in additionto said ring nitrogen atom, wherein the 0-2 additional heteroatoms areindependently selected from the group consisting of N, O and S;

wherein said 4 to 9 membered heterocyclyl may be substituted withC₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, halo, oxo, cyano, hydroxyl, —OR⁵,—O—C₁₋₄alkyl-C(O)OR⁵, cycloalkyl, heteroaryl, heterocyclyl, —C(O)OR⁵,—C(O)N(R⁵)(R⁶), —C(O)N(R⁵)(OR⁶), —C(O)R⁵, —C(O)—C₁₋₄alkyl-N(R⁵)(R⁶),—C(O)—C₁₋₄alkyl—O—C₁₋₄alkyl, —C(O)N(R⁵)—S(O)₂(R⁶), —C(O)N(R⁵)—OR⁶,—C(O)N(R⁵)S(O)₂N(R⁵)(R⁶), —C(O)N(R⁵)—C₁₋₄alkyl-C(O)OR⁶, —N(R⁵)(R⁶),—N(R⁵)—C₁₋₄alkyl—OR⁶, —N(R⁵)C(O)R⁶, —N(R⁵)C(O)OR⁶, —N(R⁵)S(O)₂R⁶,—N(R⁵)C(O)—NH(R⁶), —N(R⁵)—C₁₋₄alkyl-C(O)—NH(R⁶), —SR⁵, —S(O)₂R⁵, or—S(O)₂—N(R⁵)(R⁶);

wherein said C₁₋₄alkyl may be substituted with —OH, —O—C₁₋₄alkyl,—C(O)OR⁵, —C(O)N(R⁵)(R⁶), —N(R⁵)(R⁶), —N(R⁵)C(O)OR⁶, heterocyclyl,heteroaryl, cycloalkyl, or halo;

wherein said heteroaryl may be substituted with C₁₋₄alkyl, halo, cyano,—CF₃, alkoxy or hydroxyl;

wherein said heterocyclyl may be substituted with C₁₋₄alkyl, oxo, halo,amino, alkoxy, or hydroxyl;

wherein said C₂₋₄alkenyl and said C₂₋₄alkynyl may be independentlysubstituted with oxo, heterocyclyl, hydroxyl, or halo;

wherein R⁵ and R⁶ are each independently H, C₁₋₄alkyl, cycloalkyl, orheterocyclyl, wherein said C₁₋₄alkyl may be substituted with halo orhydroxyl; or alternatively, R⁵ and R⁶ are linked together to form a 5 to7 membered ring.

Particularly,

is a 4 to 9 membered heterocyclyl bonded to the rest of the moleculethrough a ring nitrogen atom and containing 0 heteroatoms in addition tosaid ring nitrogen atom,

wherein said 4 to 9 membered heterocyclyl may be substituted withC₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, halo, oxo, cyano, hydroxyl, —OR⁵,—O—C₁₋₄alkyl-C(O)OR⁵, cycloalkyl, heteroaryl, heterocyclyl, —C(O)OR⁵,—C(O)N(R⁵)(R⁶), —C(O)N(R⁵)(OR⁶), —C(O)R⁵, —C(O)—C₁₋₄alkyl-N(R⁵)(R⁶),—C(O)—C₁₋₄alkyl—O—C₁₋₄alkyl, —C(O)N(R⁵)—S(O)₂(R⁶), —C(O)N(R⁵)—OR⁶,—C(O)N(R⁵)S(O)₂N(R⁵)(R⁶), —C(O)N(R⁵)—C₁₋₄alkyl-C(O)OR⁶, —N(R⁵)(R⁶),—N(R⁵)—C₁₋₄alkyl—OR⁶, —N(R⁵)C(O)R⁶, —N(R⁵)C(O)OR⁶, —N(R⁵)S(O)₂R⁶,—N(R⁵)C(O)—NH(R⁶), —N(R⁵)—C₁₋₄alkyl-C(O)—NH(R⁶), —SR⁵, —S(O)₂R⁵, or—S(O)₂—N(R⁵)(R⁶);

wherein said C₁₋₄alkyl may be substituted with —OH, —O—C₁₋₄alkyl,—C(O)OR⁵, —C(O)N(R⁵)(R⁶), —N(R⁵)(R⁶), —N(R⁵)C(O)OR⁶, heterocyclyl,heteroaryl, cycloalkyl, or halo;

wherein said heteroaryl may be substituted with C₁₋₄alkyl, halo, cyano,—CF₃, alkoxy or hydroxyl;

wherein said heterocyclyl may be substituted with C₁₋₄alkyl, oxo, halo,amino, alkoxy, or hydroxyl;

wherein said C₂₋₄alkenyl and said C₂₋₄alkynyl may be independentlysubstituted with oxo, heterocyclyl, hydroxyl, or halo;

wherein R⁵ and R⁶ are each independently H, C₁₋₄alkyl, cycloalkyl, orheterocyclyl, wherein said C₁₋₄alkyl may be substituted with halo orhydroxyl; or alternatively R⁵ and R⁶ are linked together to form a 5 to7 membered ring.

Particularly,

is a 4 to 9 membered heterocyclyl bonded to the rest of the moleculethrough a ring nitrogen atom and containing 1 heteroatom in addition tosaid ring nitrogen atom, wherein the 1 additional heteroatom isindependently selected from the group consisting of N, O and S;

wherein said 4 to 9 membered heterocyclyl may be substituted withC₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, halo, oxo, cyano, hydroxyl, —OR⁵,—O—C₁₋₄alkyl-C(O)OR⁵, cycloalkyl, heteroaryl, heterocyclyl, —C(O)OR⁵,—C(O)N(R⁵)(R⁶), —C(O)N(R⁵)(OR⁶), —C(O)R⁵, —C(O)—C₁₋₄alkyl-N(R⁵)(R⁶),—C(O)—C₁₋₄alkyl—O—C₁₋₄alkyl, —C(O)N(R⁵)—S(O)₂(R⁶), —C(O)N(R⁵)—OR⁶,—C(O)N(R⁵)S(O)₂N(R⁵)(R⁶), —C(O)N(R⁵)—C₁₋₄alkyl-C(O)OR⁶, —N(R⁵)(R⁶),—N(R⁵)—C₁₋₄alkyl—OR⁶, —N(R⁵)C(O)R⁶, —N(R⁵)C(O)OR⁶, —N(R⁵)S(O)₂R⁶,—N(R⁵)C(O)—NH(R⁶), —N(R⁵)—C₁₋₄alkyl-C(O)—NH(R⁶), —SR⁵, —S(O)₂R⁵, or—S(O)₂—N(R⁵)(R⁶);

wherein said C₁₋₄alkyl may be substituted with —OH, —O—C₁₋₄alkyl,—C(O)OR⁵, —C(O)N(R⁵)(R⁶), —N(R⁵)(R⁶), —N(R⁵)C(O)OR⁶, heterocyclyl,heteroaryl, cycloalkyl, or halo;

wherein said heteroaryl may be substituted with C₁₋₄alkyl, halo, cyano,—CF₃, alkoxy or hydroxyl;

wherein said heterocyclyl may be substituted with C₁₋₄alkyl, oxo, halo,amino, alkoxy, or hydroxyl;

wherein said C₂₋₄alkenyl and said C₂₋₄alkynyl may be independentlysubstituted with oxo, heterocyclyl, hydroxyl, or halo;

wherein R⁵ and R⁶ are each independently —H, C₁₋₄alkyl, cycloalkyl, orheterocyclyl, wherein said C₁₋₄alkyl may be substituted with halo orhydroxyl; or alternatively R⁵ and R⁶ are linked together to form a 5 to7 membered ring.

Particularly,

is a 4 to 9 membered heterocyclyl bonded to the rest of the moleculethrough a ring nitrogen atom and containing 2 heteroatoms in addition tosaid ring nitrogen atom, wherein the 2 additional heteroatom areindependently selected from the group consisting of N, O and S;

wherein said 4 to 9 membered heterocyclyl may be substituted withC₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, halo, oxo, cyano, hydroxyl, —OR⁵,—O—C₁₋₄alkyl-C(O)OR⁵, cycloalkyl, heteroaryl, heterocyclyl, —C(O)OR⁵,—C(O)N(R⁵)(R⁶), —C(O)N(R⁵)(OR⁶), —C(O)R⁵, —C(O)—C₁₋₄alkyl-N(R⁵)(R⁶),—C(O)—C₁₋₄alkyl—O—C₁₋₄alkyl, —C(O)N(R⁵)—S(O)₂(R⁶), —C(O)N(R⁵)—OR⁶,—C(O)N(R⁵)S(O)₂N(R⁵)(R⁶), —C(O)N(R⁵)—C₁₋₄alkyl-C(O)OR⁶, —N(R⁵)(R⁶),—N(R⁵)—C₁₋₄alkyl—OR⁶, —N(R⁵)C(O)R⁶, —N(R⁵)C(O)OR⁶, —N(R⁵)S(O)₂R⁶,—N(R⁵)C(O)—NH(R⁶), —N(R⁵)—C₁₋₄alkyl-C(O)—NH(R⁶), —SR⁵, —S(O)₂R⁵, or—S(O)₂—N(R⁵)(R⁶);

wherein said C₁₋₄alkyl may be substituted with —OH, —O—C₁₋₄alkyl,—C(O)OR⁵, —C(O)N(R⁵)(R⁶), —N(R⁵)(R⁶), —N(R⁵)C(O)OR⁶, heterocyclyl,heteroaryl, cycloalkyl, or halo;

wherein said heteroaryl may be substituted with C₁₋₄alkyl, halo, cyano,—CF₃, alkoxy or hydroxyl;

wherein said heterocyclyl may be substituted with C₁₋₄alkyl, oxo, halo,amino, alkoxy, or hydroxyl;

wherein said C₂₋₄alkenyl and said C₂₋₄alkynyl may be independentlysubstituted with oxo, heterocyclyl, hydroxyl, or halo;

wherein R⁵ and R⁶ are each independently —H, C₁₋₄alkyl, cycloalkyl, orheterocyclyl, wherein said C₁₋₄alkyl may be substituted with halo orhydroxyl; or alternatively, R⁵ and R⁶ are linked together to form a 5 to7 membered ring.

Particularly,

is a 4 to 9 membered heterocyclyl bonded to the rest of the moleculethrough a ring nitrogen atom and containing 0 heteroatoms in addition tosaid ring nitrogen atom,

wherein said 4 to 9 membered heterocyclyl is selected from

Particularly,

is a 4 to 9 membered heterocyclyl bonded to the rest of the moleculethrough a ring nitrogen atom and containing 1 heteroatom in addition tosaid ring nitrogen atom, wherein the 1 additional heteroatom isindependently selected from the group consisting of N, O and S;

wherein said 4 to 9 membered heterocyclyl is selected from

Particularly,

is a 4 to 9 membered heterocyclyl bonded to the rest of the moleculethrough a ring nitrogen atom and containing 2 heteroatoms in addition tosaid ring nitrogen atom, wherein the 2 additional heteroatom areindependently selected from the group consisting of N, O and S;

wherein said 4 to 9 membered heterocyclyl is

More particularly, the N-containing heterocyclyl is independentlyselected from:

Particularly, the present invention includes a compound of Formula (I)wherein

X is —CH—;

R₁ is —CF₃, —Br, or —I;

R₂ is —CF₃, hydroxyl, —OCH₃, or —Cl; and

R₃ is —H, halo, or cyano.

Particularly, the present invention includes a compound of Formula (I)wherein

X is —CH—;

R₁ is —CF₃, —Br, or —I;

R₂ is —CF₃, hydroxyl, —OCH₃, or —Cl; and

R₃ is halo, or cyano.

Particularly, the present invention includes a compound of Formula (I)wherein

X is —CH—;

R₁ is —CF₃, —Br, or —I;

R₂ is —CF₃, hydroxyl, —OCH₃, or —Cl; and

R₃ is —H.

Particularly, the present invention includes a compound of Formula (I)wherein

X is —CH—;

R₁ is —CF₃;

R₂ is —CF₃, —OCH₃, or —Cl; and

R₃ is —H.

More particularly, an example of the present invention includescompounds of Formula (I) wherein

X is —CH—;

R₁ is —C(O)—C₁₋₂alkyl, —Cl, —Br, —I, C₁₋₃alkyl, or C₃₋₅cycloalkyl;wherein said —C₁₋₃alkyl may be substituted with halo;

R₂ is —F, —Cl, —Br, cyclopropyl, C₁₋₂alkoxy or hydroxyl; wherein saidC₁₋₃alkyl may be substituted with halo or hydroxyl;

R₃ is —H, halo, or cyano; and

is selected from

More particularly, an example of the present invention includescompounds of Formula (I) wherein

X is —CH—;

R₁ is —C(O)—CH₃, —Cl, —Br, —I, —CF₃, or cyclopropyl;

R₂ is —F, —Cl, —Br, cyclopropyl, C₁₋₃alkyl, C₁₋₂alkoxy or hydroxyl;wherein said C₁₋₃alkyl may be substituted with hydroxyl or halo;

R₃ is —H, halo, or cyano; and

is selected from

More particularly, an example of the present invention includescompounds of Formula (I) wherein

X is —CH—;

R₁ is —CF₃, —Br, or —I;

R₂ is —CF₃, hydroxyl, —OCH₃, or —Cl;

R₃ is —H, halo, or cyano; and

is selected from

More particularly, an example of the present invention includescompounds of Formula (I) wherein

X is —CH—;

R₁ is —CF₃;

R₂ is —CF₃, —OCH₃, or —Cl;

R₃ is —H; and

is selected from

More particularly, an example of the present invention includescompounds of Formula (I) wherein

X is —CH;

R₁ is —CF₃;

R₂ is —CF₃ or —Cl;

R₃ is —H; and

is selected from

Preferred embodiments of the present invention include compounds ofFormula (I) wherein

is selected from

More preferred embodiments of the present invention include compounds ofFormula (I) wherein

is selected from

More particularly, an example of the present invention includescompounds of Formula (I) wherein

X is —CH—;

R₁ is —C(O)—C₁₋₂alkyl, —Cl, —Br, —I, C₁₋₃alkyl, or C₃₋₅cycloalkyl;wherein said C₁₋₃alkyl may be substituted with halo;

R₂ is —F, —Cl, —Br, cyclopropyl, C₁₋₃alkyl, C₁₋₂alkoxy or hydroxyl;wherein said C₁₋₃alkyl may be substituted with halo or hydroxyl;

R₃ is —H, halo, or cyano; and

is selected from

More particularly, an example of the present invention includescompounds of Formula (I) wherein

X is —CH—;

R₁ is —C(O)—CH₃, —Cl, —Br, —I, —CF₃, or cyclopropyl;

R₂ is —F, —Cl, —Br, cyclopropyl, C₁₋₃alkyl, C₁₋₂alkoxy or hydroxyl;wherein said C₁₋₃alkyl may be substituted with halo or hydroxyl;

R₃ is —H, halo, or cyano; and

is selected from

More particularly, an example of the present invention includescompounds of Formula (I) wherein

X is —CH—;

R₁ is —CF₃, —Br, or —I;

R₂ is —CF₃, hydroxyl, —OCH₃, or —Cl;

R₃ is —H, halo, or cyano; and and

is selected from

More particularly, an example of the present invention includescompounds of Formula (I) wherein

X is —CH;

R₁ is —CF₃;

R₂ is —CF₃, —OCH₃, or —Cl;

R₃ is —H; and

is selected from

More particularly, an example of the present invention includescompounds of Formula (I) wherein

X is —CH—;

R₁ is —CF₃;

R₂ is —CF₃ or —Cl;

R₃ is —H; and

is selected from

More particularly, an example of the present invention includescompounds of Formula (I) wherein

X is —CH—;

R₁ is —C(O)—C₁₋₂alkyl, —Cl, —Br, —I, C₁₋₃alkyl, or C₃₋₅cycloalkyl;wherein said C₁₋₃alkyl may be substituted with halo;

R₂ is —F, —Cl, —Br, cyclopropyl, C₁₋₃alkyl, C₁₋₂alkoxy or hydroxyl;wherein said C₁₋₃alkyl may be substituted with halo or hydroxyl;

R₃ is —H, halo, or cyano; and

is selected from

More particularly, an example of the present invention includescompounds of Formula (I) wherein

X is —CH—;

R₁ is —C(O)—CH₃, —Cl, —Br, —I, —CF₃, or cyclopropyl;

R₂ is —F, —Cl, —Br, cyclopropyl, C₁₋₃alkyl, C₁₋₂alkoxy or hydroxyl;wherein said C₁₋₃alkyl may be substituted with halo or hydroxyl;

R₃ is —H, halo, or cyano; and

is selected from

More particularly, an example of the present invention includescompounds of Formula (I) wherein

X is —CH—;

R₁ is —CF₃, —Br, or —I;

R₂ is —CF₃, hydroxyl, —OCH₃, or —Cl;

R₃ is —H, halo, or cyano; and

is selected from

More particularly, an example of the present invention includescompounds of Formula (I) wherein

X is —CH—;

R₁ is —CF₃;

R₂ is —CF₃, —OCH₃, or —Cl;

R₃ is —H; and

is selected from

More particularly, an example of the present invention includescompounds of Formula (I) wherein

X is —CH—;

R₁ is —CF₃;

R₂ is —CF₃ or —Cl;

R₃ is —H; and

is selected from

It is an embodiment of the present invention to provide a compoundselected from:

-   1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carboxylic    acid;-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one;-   1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carboxylic    acid;-   1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carboxylic    acid;-   1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carboxylic    acid;-   2-(3-(S)-Amino-piperidin-1-yl)-5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one;-   5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[1,4]diazepan-1-yl-thiazol-4-one;-   5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-methoxy-ethyl)-piperazin-1-yl]-thiazol-4-one;-   2-(3-(R)-Amino-pyrrolidin-1-yl)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one;-   5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(S)-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-thiazol-4-one;-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-methoxy-ethyl)-piperazin-1-yl]-thiazol-4-one;-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(5-methyl-2S,5S-diaza-bicyclo[2.2.1]hept-2-yl)-thiazol-4-one;-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[5-(2-hydroxy-ethyl)-2S,5S-diaza-bicyclo[2.2.1]hept-2-yl]-thiazol-4-one;-   2-(4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazin-1-yl)-N,N-dimethyl-acetamide;-   2-(3-Amino-azetidin-1-yl)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one;-   5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(8-methyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-thiazol-4-one;-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2-hydroxymethyl-piperazin-1-yl)-thiazol-4-one;-   5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(1H-tetrazol-5-yl)-piperidin-1-yl]-thiazol-4-one;-   5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(6-hydroxy-[1,4]diazepan-1-yl)-thiazol-4-one;-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one;-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-((2S)-hydroxymethyl-morpholin-4-yl)-thiazol-4-one;-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3(R)-hydroxymethyl-morpholin-4-yl)-thiazol-4-one;-   5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3(R)-hydroxymethyl-morpholin-4-yl)-thiazol-4-one;-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-methyl-1H-indazol-5-ylmethylene]-2-(3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one;-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-chloro-1H-indazol-5-ylmethylene]-2    (3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one;-   4-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]morpholine-2-carboxylic    acid;-   1-[5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-1,2,3,6-tetrahydropyridine-4-carboxylic    acid;-   Methyl{1-[5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-5-(R)-(hydroxymethyl)pyrrolidin-3-(R)-yl}carbamate;-   1-[4-Chloro-2-(trifluoromethyl)benzyl]-5-{[2-(4-methylpiperazin-1-yl)-4-oxo-1,3-thiazol-5(4H)-ylidene]methyl}-1H-indazole-3-carbonitrile;-   N-{1-[(3R,5R)-5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-5-(hydroxymethyl)pyrrolidin-3-yl}acetamide;    and-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-(S)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one.

Particularly, the present invention provides a compound selected from:

-   1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carboxylic    acid;-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one;-   1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carboxylic    acid;-   1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carboxylic    acid;-   2-(3-(S)-Amino-piperidin-1-yl)-5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one;-   5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[1,4]diazepan-1-yl-thiazol-4-one;-   5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-methoxy-ethyl)piperazin-1-yl]-thiazol-4-one;-   2-(3-(R)-Amino-pyrrolidin-1-yl)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one;-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(5-methyl-2S,5S-diaza-bicyclo[2.2.1]hept-2-yl)-thiazol-4-one;-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[5-(2-hydroxy-ethyl)-2S,5S-diaza-bicyclo[2.2.1]hept-2-yl]-thiazol-4-one;-   2-(3-Amino-azetidin-1-yl)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one;-   5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(6-hydroxy-[1,4]diazepan-1-yl)-thiazol-4-one;-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one;-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-((2S)-hydroxymethyl-morpholin-4-yl)-thiazol-4-one;-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3(R)-hydroxymethyl-morpholin-4-yl)-thiazol-4-one;-   5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3(R)-hydroxymethyl-morpholin-4-yl)-thiazol-4-one;-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-methyl-1H-indazol-5-ylmethylene]-2-(3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one;-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-chloro-1H-indazol-5-ylmethylene]-2    (3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one;-   4-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]morpholine-2-carboxylic    acid;-   1-[5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-1,2,3,6-tetrahydropyridine-4-carboxylic    acid;-   Methyl{1-[5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-5-(R)-(hydroxymethyl)pyrrolidin-3-(R)-yl}carbamate;-   1-[4-Chloro-2-(trifluoromethyl)benzyl]-5-{[2-(4-methylpiperazin-1-yl)-4-oxo-1,3-thiazol-5(4H)-ylidene]methyl}-1H-indazole-3-carbonitrile;-   N-{1-[(3R,5R)-5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-5-(hydroxymethyl)pyrrolidin-3-yl}acetamide;    and-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-(S)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one.

More particularly, the present invention provides a compound selectedfrom:

-   1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carboxylic    acid;-   1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carboxylic    acid;-   2-(3-(S)-Amino-piperidin-1-yl)-5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one;-   5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[1,4]diazepan-1-yl-thiazol-4-one;-   2-(3-Amino-azetidin-1-yl)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one;-   5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(6-hydroxy-[1,4]diazepan-1-yl)thiazol-4-one;-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one;-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-((2S)-hydroxymethyl-morpholin-4-yl)-thiazol-4-one;-   5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3(R)-hydroxymethyl-morpholin-4-yl)-thiazol-4-one;-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-methyl-1H-indazol-5-ylmethylene]-2-(3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one;-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-chloro-1H-indazol-5-ylmethylene]-2    (3-(R)-hydroxymethyl-piperazin-1-yl)thiazol-4-one;-   4-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]morpholine-2-carboxylic    acid;-   1-[5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-1,2,3,6-tetrahydropyridine-4-carboxylic    acid;-   Methyl{1-[5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-5-(R)-(hydroxymethyl)pyrrolidin-3-(R)-yl}carbamate;-   1-[4-Chloro-2-(trifluoromethyl)benzyl]-5-{[2-(4-methylpiperazin-1-yl)-4-oxo-1,3-thiazol-5(4H)-ylidene]methyl}-1H-indazole-3-carbonitrile;    and-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-(S)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one.

Another aspect of the present invention features a pharmaceuticalcomposition comprising at least one compound of Formula (I) and at leastone pharmaceutically acceptable carrier. Particularly, a pharmaceuticalcomposition of the present invention can further comprise at least oneadditional agent, drug, medicament, antibody and/or inhibitor fortreating, ameliorating or preventing the progression of an ERR-αmediated disease.

A pharmaceutical composition of the present invention comprises acompound selected from:

-   1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carboxylic    acid;-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one;-   1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carboxylic    acid;-   1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carboxylic    acid;-   1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carboxylic    acid;-   2-(3-(S)-Amino-piperidin-1-yl)-5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one;-   5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[1,4]diazepan-1-yl-thiazol-4-one;-   5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-methoxy-ethyl)-piperazin-1-yl]-thiazol-4-one;-   2-(3-(R)-Amino-pyrrolidin-1-yl)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one;-   5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(S)-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-thiazol-4-one;-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-methoxy-ethyl)-piperazin-1-yl]-thiazol-4-one;-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(5-methyl-2S,5S-diaza-bicyclo[2.2.1]hept-2-yl)-thiazol-4-one;-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[5-(2-hydroxy-ethyl)-2S,5S-diaza-bicyclo[2.2.1]hept-2-yl]-thiazol-4-one;-   2-(4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazin-1-yl)-N,N-dimethyl-acetamide;-   2-(3-Amino-azetidin-1-yl)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one;-   5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(8-methyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-thiazol-4-one;-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2-hydroxymethyl-piperazin-1-yl)-thiazol-4-one;-   5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(1H-tetrazol-5-yl)-piperidin-1-yl]-thiazol-4-one;-   5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(6-hydroxy-[1,4]diazepan-1-yl)-thiazol-4-one;-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one;-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-((2S)-hydroxymethyl-morpholin-4-yl)-thiazol-4-one;-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3(R)-hydroxymethyl-morpholin-4-yl)-thiazol-4-one;-   5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3(R)-hydroxymethyl-morpholin-4-yl)-thiazol-4-one;-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-methyl-1H-indazol-5-ylmethylene]-2-(3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one;-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-chloro-1H-indazol-5-ylmethylene]-2    (3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one;-   4-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]morpholine-2-carboxylic    acid;-   1-[5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-1,2,3,6-tetrahydropyridine-4-carboxylic    acid;-   Methyl{1-[5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-5-(R)-(hydroxymethyl)pyrrolidin-3-(R)-yl}carbamate;-   1-[4-Chloro-2-(trifluoromethyl)benzyl]-5-{[2-(4-methylpiperazin-1-yl)-4-oxo-1,3-thiazol-5(4H)-ylidene]methyl}-1H-indazole-3-carbonitrile;-   N-{1-[(3R,5R)-5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-5-(hydroxymethyl)pyrrolidin-3-yl}acetamide;    and-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-(S)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one.

Particularly, a pharmaceutical composition of the present inventioncomprises at least a compound selected from:

-   1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carboxylic    acid;-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one;-   1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carboxylic    acid;-   1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carboxylic    acid;-   2-(3-(S)-Amino-piperidin-1-yl)-5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one;-   5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[1,4]diazepan-1-yl-thiazol-4-one;-   5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-methoxy-ethyl)-piperazin-1-yl]-thiazol-4-one;-   2-(3-(R)-Amino-pyrrolidin-1-yl)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one;-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(5-methyl-2S,5S-diaza-bicyclo[2.2.1]hept-2-yl)-thiazol-4-one;-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[5-(2-hydroxy-ethyl)-2S,5S-diaza-bicyclo[2.2.1]hept-2-yl]-thiazol-4-one;-   2-(3-Amino-azetidin-1-yl)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one;-   5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(6-hydroxy-[1,4]diazepan-1-yl)-thiazol-4-one;-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one;-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-((2S)-hydroxymethyl-morpholin-4-yl)-thiazol-4-one;-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3(R)-hydroxymethyl-morpholin-4-yl)-thiazol-4-one;-   5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3(R)-hydroxymethyl-morpholin-4-yl)-thiazol-4-one;-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-methyl-1H-indazol-5-ylmethylene]-2-(3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one;-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-chloro-1H-indazol-5-ylmethylene]-2    (3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one;-   4-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]morpholine-2-carboxylic    acid;-   1-[5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-1,2,3,6-tetrahydropyridine-4-carboxylic    acid;-   Methyl{1-[5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-5-(R)-(hydroxymethyl)pyrrolidin-3-(R)-yl}carbamate;-   1-[4-Chloro-2-(trifluoromethyl)benzyl]-5-{[2-(4-methylpiperazin-1-yl)-4-oxo-1,3-thiazol-5(4H)-ylidene]methyl}-1H-indazole-3-carbonitrile;-   N-{1-[(3R,5R)-5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-5-(hydroxymethyl)pyrrolidin-3-yl}acetamide;    and-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-(S)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one.

More particularly, a pharmaceutical composition of the present inventioncomprises at least a compound selected from:

-   1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carboxylic    acid;-   1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carboxylic    acid;-   2-(3-(S)-Amino-piperidin-1-yl)-5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one;-   5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[1,4]diazepan-1-yl-thiazol-4-one;-   2-(3-Amino-azetidin-1-yl)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one;-   5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(6-hydroxy-[1,4]diazepan-1-yl)-thiazol-4-one;-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one;-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-((2S)-hydroxymethyl-morpholin-4-yl)-thiazol-4-one;-   5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3(R)-hydroxymethyl-morpholin-4-yl)-thiazol-4-one;-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-methyl-1H-indazol-5-ylmethylene]-2-(3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one;-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-chloro-1H-indazol-5-ylmethylene]-2    (3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one;-   4-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]morpholine-2-carboxylic    acid;-   1-[5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-1,2,3,6-tetrahydropyridine-4-carboxylic    acid;-   Methyl{1-[5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-5-(R)-(hydroxymethyl)pyrrolidin-3-(R)-yl}carbamate;-   1-[4-Chloro-2-(trifluoromethyl)benzyl]-5-{[2-(4-methylpiperazin-1-yl)-4-oxo-1,3-thiazol-5(4H)-ylidene]methyl}-1H-indazole-3-carbonitrile;    and-   5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-(S)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one.

It is an embodiment of the present invention to provide a compoundselected from:

The present invention also features a method of treating a subjectsuffering from or diagnosed with a disease, disorder, or conditionmediated by ERR-α activity, comprising administering to the subject atherapeutically effective amount of at least one compound of Formula(I).

The present invention also features a method for preventing orinhibiting the progression of an ERR-α-mediated condition in a subjectin need thereof, comprising administering to said subject atherapeutically effective amount of at least one compound of Formula(I).

The present invention also features a method for treating a prediabeticcondition in a subject in need thereof, comprising administering to saidsubject a therapeutically effective amount of at least one compound ofFormula (I).

Such disease, disorder, or condition can include, but is not limited toankylosing spondylitis, artherosclerosis, arthritis (such as rheumatoidarthritis, infectious arthritis, childhood arthritis, psoriaticarthritis, reactive arthritis), bone-related diseases (including thoserelated to bone formation), breast cancer (including those unresponsiveto anti-estrogen therapy), cardiovascular disorders, cartilage-relateddisease (such as cartilage injury/loss, cartilage degeneration, andthose related to cartilage formation), chondrodysplasia, chondrosarcoma,chronic back injury, chronic bronchitis, chronic inflammatory airwaydisease, chronic obstructive pulmonary disease, diabetes, disorders ofenergy homeostasis, gout, pseudogout, lipid disorders, metabolicsyndrome, multiple myeloma, obesity, osteoarthritis, osteogenesisimperfecta, osteolytic bone metastasis, osteomalacia, osteoporosis,Paget's disease, periodontal disease, polymyalgia rheumatica, Reiter'ssyndrome, repetitive stress injury, hyperglycemia, elevated bloodglucose level, and insulin resistance.

According to one aspect of the invention, the disclosed compounds andcompositions are useful for the amelioration of symptoms associatedwith, the treatment of, and preventing and/or inhibiting the progressionof, the following conditions and diseases: bone-related disease, boneformation, cartilage formation, cartilage loss, cartilage degeneration,cartilage injury, ankylosing spondylitis, chronic back injury, gout,osteoporosis, osteolytic bone metastasis, multiple myeloma,chondrosarcoma, chondrodysplasia, osteogenesis imperfecta, osteomalacia,Paget's disease, polymyalgia rheumatica, pseudogout, arthritis,rheumatoid arthritis, infectious arthritis, osteoarthritis, psoriaticarthritis, reactive arthritis, childhood arthritis, Reiter's syndrome,and repetitive stress injury.

According to another aspect of the invention, the disclosed compoundsand compositions are useful for the amelioration of symptoms associatedwith, the treatment of, and preventing and/or inhibiting the progressionof, the following conditions and diseases: periodontal disease, chronicinflammatory airway disease, chronic bronchitis, and chronic obstructivepulmonary disease.

According to a further aspect of the invention, the disclosed compoundsand compositions are useful for the amelioration of symptoms associatedwith, the treatment of, and preventing and/or inhibiting the progressionof breast cancer.

According to yet another aspect of the invention, the disclosedcompounds and compositions are useful for the amelioration of symptomsassociated with, the treatment of, and preventing and/or inhibiting theprogression of, the following conditions and diseases: metabolicsyndrome, obesity, disorders of energy homeostasis, diabetes, lipiddisorders, cardiovascular disorders, artherosclerosis, hyperglycemia,elevated blood glucose level, and insulin resistance.

Particularly, a method of the present invention comprises administeringto the subject a therapeutically effective amount of (a) at least onecompound of Formula (I); and (b) at least one additional agent selectedfrom an anti-diabetic agent, an anti-obesity agent, a lipid loweringagent, an anti-thrombotic agent, direct thrombin inhibitor, and a bloodpressure lowering agent, said administration being in any order. Moreparticularly, the additional agent in (b) is an anti-obesity agentselected from CB1 antagonists, monoamine reuptake inhibitors, MTPinhibitors and lipase inhibitors. More particularly, the additionalagent in (b) is an anti-diabetic agent selected from metformin, DPP-IVinhibitors, GLP-1 mimetics, glucokinase modulators, glucagonantagonists, SGLT2 inhibitors, PPARγ agonists and GPR119 modulators.More particularly, the additional agent in (b) is selected fromMetformin, Sitagliptin and Pioglitazone.

The present invention also features a method for treating or inhibitingthe progression of one or more ERR-α-mediated conditions, said methodcomprising administering to a patient in need of treatment apharmaceutically effective amount of a composition of the invention.

It is a further embodiment of the invention to provide a process formaking a pharmaceutical composition comprising admixing any of thecompounds according to Formula (I) and a pharmaceutically acceptablecarrier.

The invention also features pharmaceutical compositions which include,without limitation, one or more of the disclosed compounds, andpharmaceutically acceptable carriers or excipients.

In a further embodiment of the invention, a method for treating orameliorating an ERR-α-mediated condition in a subject in need thereofcomprises administering to the subject a therapeutically effectiveamount of at least one compound of Formula (I), wherein thetherapeutically effective amount of the compound of Formula (I) is fromabout 0.1 mg/dose to about 5000 mg/dose. In particular, thetherapeutically effective amount of the compound of Formula (I) is fromabout 0.5 mg/dose to about 1000 mg/dose. More particularly, thetherapeutically effective amount of the compound of Formula (I) is fromabout 1 mg/dose to about 100 mg/dose. In a further embodiment of theinvention, the number of doses per day of a compound of Formula (I) isfrom 1 to 3 doses. In a further embodiment of the invention, thetherapeutically effective amount of the compound of Formula (I) is fromabout 0.001 mg/kg/day to about 30 mg/kg/day. More particularly, thetherapeutically effective amount of the compound of Formula (I) is fromabout 0.01 mg/kg/day to about 2 mg/kg/day.

In a further embodiment of the invention, a method for preventing orinhibiting the progression of an ERR-α-mediated condition in a subjectin need thereof comprises administering to the subject a therapeuticallyeffective amount of at least one compound of Formula (I), wherein thetherapeutically effective amount of the compound of Formula (I) is fromabout 0.1 mg/dose to about 5000 mg/dose. In particular, thetherapeutically effective amount of the compound of Formula (I) is fromabout 1 mg/dose to about 100 mg/dose. In a further embodiment of theinvention, the number of doses per day of a compound of Formula (I) isfrom 1 to 3 doses. In a further embodiment of the invention, thetherapeutically effective amount of the compound of Formula (I) is fromabout 0.001 mg/kg/day to about 30 mg/kg/day. More particularly, thetherapeutically effective amount of the compound of Formula (I) is fromabout 0.01 mg/kg/day to about 2 mg/kg/day.

In yet another embodiment of the invention, a method for treating aprediabetic condition in a subject in need thereof, comprisesadministering to said subject a therapeutically effective amount of atleast one compound of Formula (I), wherein the therapeutically effectiveamount of the compound of Formula (I) is from about 0.1 mg/dose to about5000 mg/dose. In particular, the therapeutically effective amount of thecompound of Formula (I) is from about 1 mg/dose to about 100 mg/dose. Ina further embodiment of the invention, the number of doses per day of acompound of Formula (I) is from 1 to 3 doses. In a further embodiment ofthe invention, the therapeutically effective amount of the compound ofFormula (I) is from about 0.001 mg/kg/day to about 30 mg/kg/day. Moreparticularly, the therapeutically effective amount of the compound ofFormula (I) is from about 0.01 mg/kg/day to about 2 mg/kg/day.

The invention is further described below.

A) Terms

Some terms are defined below and by their usage throughout thisdisclosure.

Unless otherwise noted, “alkyl” as used herein, whether used alone or aspart of a substituent group, refers to a saturated, branched, orstraight-chain monovalent hydrocarbon radical derived by the removal ofone hydrogen atom from a single carbon atom of a parent alkane. Typicalalkyl groups include, but are not limited to, methyl; ethyls such asethanyl; propyls such as propan-1-yl, propan-2-yl, cyclopropan-1-yl;butyls such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl,2-methyl-propan-2-yl, cyclobutan-1-yl and the like. In preferredembodiments, the alkyl groups are C₁₋₆alkyl, C₁₋₄alkyl, with C₁₋₃ beingparticularly preferred. “Alkoxy” radicals are oxygen ethers formed fromthe previously described straight or branched chain alkyl groups.

The term “cycloalkyl”, as used herein, refers to a stable, saturated orpartially saturated monocyclic or bicyclic ring system containing from 3to 10 ring carbons. preferably 5 to 7 ring carbons, and more preferably3 to 5 ring carbons. Examples of such cyclic alkyl rings includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

The term “alkenyl” refers to an unsaturated branched, straight-chain orcyclic monovalent hydrocarbon radical, which has at least onecarbon-carbon double bond, derived by the removal of one hydrogen atomfrom a single carbon atom of a parent alkene. The radical may be ineither the cis or trans conformation about the double bond(s). Typicalalkenyl groups include, but are not limited to, ethenyl; propenyls suchas prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl, prop-2-en-2-yl,cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyls such asbut-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl,1-methylethenyl, etc.; and the like.

The term “alkynyl” refers to an unsaturated branched, straight-chain orcyclic monovalent hydrocarbon radical, which has at least onecarbon-carbon triple bond, derived by the removal of one hydrogen atomfrom a single carbon atom of a parent alkyne. Typical alkynyl groupsinclude, but are not limited to, ethynyl; propynyls such asprop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such as but-1-yn-1-yl,but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.

The term “heteroaryl” refers to a monovalent heteroaromatic radicalderived by the removal of one hydrogen atom from a single atom of aparent heteroaromatic ring system. Typical heteroaryl groups includemonocyclic and bicyclic systems where one or both rings areheteroaromatic. Heteroaromatic rings may contain 1-4 heteroatomsselected from O, N, and S. Examples include but are not limited to,radicals derived from carbazole, imidazole, indazole, indole,indolizine, isoindole, isoquinoline, isothiazole, isoxazole,naphthyridine, oxadiazole, oxazole, purine, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline,quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole,thiophene, triazole, xanthene, and the like.

The term “aryl”, as used herein, refers to carbocyclic aromatic groupscomprising 6- to 14-carbon atoms. Typical aryl groups include but arenot limited to, a stable six-membered monocyclic, a ten-memberedbicyclic or a fourteen-membered tricyclic aromatic ring system. Examplesof aryl groups include, but are not limited to, phenyl or naphthalenyl.

The term “heterocyclyl” or “heterocycle” is a 3- to 12-member saturated,or partially saturated single or fused ring system and preferably a 4 to9 member saturated, or partially saturated single or fused ring system,which consists of carbon atoms and from 1 to 4 heteroatoms selected fromN, O and S. The heterocyclyl group may be attached at any heteroatom orcarbon atom, which results in the creation of a stable structure.Example of heterocyclyl groups include, but are not limited to,2-imidazoline, imidazolidine; azetidine, morpholine, oxazoline,2-pyrroline, 3-pyrroline, pyrrolidine, pyridone, pyrimidone, piperazine,piperidine, indoline, tetrahydrofuran, 2-pyrroline, 3-pyrroline,2-imidazoline, 2-pyrazoline, indolinone, tetrahydroquinoline,tetrahydroquinazoline, and the like.

For the purpose of clarification, in this application

means N-containing heterocyclyl.

As used herein, “halo” or “halogen” shall mean chlorine, bromine,fluorine and iodine. “Halo substituted” shall mean a group substitutedwith at least one halogen atom, preferably substituted with a least onefluoro atom. Suitable examples include, but are not limited to —CF₃,—CH₂—CHF₂, —CH₂—CF₃, and the like.

The term “oxo” whether used alone or as part of a substituent grouprefers to an O═ to either a carbon or a sulfur atom. For example,phthalimide and saccharin are examples of compounds with oxosubstituents.

The term “cis-trans isomer” refers to stereoisomeric olefins orcycloalkanes (or hetero-analogues), which differ in the positions ofatoms (or groups) relative to a reference plane: in the cis-isomer theatoms are on the same side; in the trans-isomer they are on oppositesides.

The term “substituted” refers to a radical in which one or more hydrogenatoms are each independently replaced with the same or differentsubstituent(s). A substituted group comprising alkyl, cycloalkyl, aryl,heteroaryl, heterocyclyl may have one or more substituents, preferablyfrom one to five substituents, more preferably from one to threesubstituents, most preferably from one to two substituents,independently selected from the list of substituents.

With reference to substituents, the term “independently” means that whenmore than one of such substituent is possible, such substituents may bethe same or different from each other.

The term “composition” is intended to encompass a product comprising thespecified ingredients in the specified amounts, as well as any productwhich results, directly or indirectly, from combinations of thespecified ingredients in the specified amounts.

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who is the object of treatment,observation or experiment.

It is intended that the definition of any substituent or variable at aparticular location in a molecule be independent of its definitionselsewhere in that molecule. It is understood that substituents andsubstitution patterns on the compounds of this invention can be selectedby one of ordinary skill in the art to provide compounds that arechemically stable and that can be readily synthesized by techniquesknown in the art as well as those methods set forth herein.

Metabolic disorders, diseases, or conditions include, but are notlimited to, diabetes, obesity, and associated symptoms or complicationsthereof. They include such conditions as IDDM (insulin-dependentdiabetes mellitus), NIDDM (non insulin-dependent diabetes mellitus), IGT(Impaired Glucose Tolerance), IFG (Impaired Fasting Glucose), Syndrome X(or Metabolic Syndrome), hyperglycemia, elevated blood glucose level,and insulin resistance. A condition such as IGT or IFG is also known asa “prediabetic condition” or “prediabetic state.”

Methods are known in the art for determining effective doses fortherapeutic and prophylactic purposes for the disclosed pharmaceuticalcompositions or the disclosed drug combinations, whether or notformulated in the same composition. For therapeutic purposes, the term“therapeutically effective amount” as used herein, means that amount ofeach active compound or pharmaceutical agent, alone or in combination,that elicits the biological or medicinal response in a tissue system,animal or human that is being sought by a researcher, veterinarian,medical doctor or other clinician, which includes alleviation of thesymptoms of the disease or disorder being treated. For prophylacticpurposes (i.e., inhibiting the progression of a disorder), the term“therapeutically effective amount” refers to that amount of each activecompound or pharmaceutical agent, alone or in combination, that treatsor inhibits in a subject the progression of a disorder as being soughtby a researcher, veterinarian, medical doctor or other clinician. Thus,the present invention provides combinations of two or more drugswherein, for example, (a) each drug is administered in an independentlytherapeutically or prophylactically effective amount; (b) at least onedrug in the combination is administered in an amount that issub-therapeutic or sub-prophylactic if administered alone, but istherapeutic or prophylactic when administered in combination with thesecond or additional drugs according to the invention; or (c) both (ormore) drugs are administered in an amount that is sub-therapeutic orsub-prophylactic if administered alone, but are therapeutic orprophylactic when administered together.

The term “pharmaceutically acceptable salt” refers to non-toxicpharmaceutically acceptable salts (Ref. International J. Pharm., 1986,33, 201-217; J. Pharm. Sci., 1997 (January), 66, 1, 1). Other salts wellknown to those in the art may, however, be useful in the preparation ofcompounds according to this invention or of their pharmaceuticallyacceptable salts. Representative organic or inorganic acids include, butare not limited to, hydrochloric, hydrobromic, hydriodic, perchloric,sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic,succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic,methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic,2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic,salicylic, saccharinic or trifluoroacetic acid. Representative organicor inorganic bases include, but are not limited to, basic or cationicsalts such as benzathine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine, procaine, aluminum, calcium, lithium,magnesium, potassium, sodium and zinc.

B) Compounds

Representative compounds of the present invention are listed in Table Ibelow:

TABLE I COM- POUND STRUCTURE # NAME

1 1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1Hindazol-5-ylmethylene]-4-oxo-4,5-dihydro- 2-yl}-piperidine-4-carboxylicacid

2 5-[1-(2,4-Bis-trifluoromethyl-benzyl)- 1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one

3 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-morpholin-4-yl- thiazol-4-one

4 5-[1-(4-Fluoro-2-trifluoromethyl- benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]- thiazol-4-one

5 2-(4-Acetyl-piperazin-1-yl)-5-[1-(4-fluoro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one

6 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-thiazol- 4-one

7 5-[1-(2,4-Bis-trifluoromethyl-benzyl)- 1H-indazol-5-ylmethylene]-2-piperazin-1-yl-thiazol-4-one

8 5-[1-(4-Chloro-2-trifluoromethyl- benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4- one

9 4-(5-{2-[4-(2-Hydroxy-ethyl)- piperazin-1-yl]-4-oxo-4H-thiazol-5-ylidenemethyl}-indazol-1-ylmethyl)-3- trifluoromethyl-benzonitrile

10 4-{5-[2-(4-Methyl-piperazin-1-yl)-4- oxo-4H-thiazol-5-ylidenemethyl]-indazol-1-ylmethyl}-3-trifluoromethyl- benzonitrile

11 1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-4-(R)-hydroxy-pyrrolidine-2-(S)-carboxylic acid

12 4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4- oxo-4,5-dihydro-thiazol-2-yl}-piperazin-2-one

13 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]- thiazol-4-one

14 5-[1-(2,4-Dichloro-benzyl)-1H- indazol-5-ylmethylene]-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-thiazol- 4-one

15 5-[1-(4-Methanesulfonyl-2- trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin- 1-yl)-thiazol-4-one

16 2-[4-(2-Hydroxy-ethyl)-piperazin-1- yl]-5-[1-(4-methanesulfonyl-2-trifluoromethyl-benzyl)-1H-indazol-5- ylmethylene]-thiazol-4-one

17 5-[1-(2-Chloro-4-methanesulfonyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4- one

18 4-{5-[1-(2-Chloro-4-methanesulfonyl-benzyl)-1H-indazol-5-ylmethylene]-4- oxo-4,5-dihydro-thiazol-2-yl}-piperazin-2-one

19 5-[1-(2-Chloro-4-methanesulfonyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]- thiazol-4-one

20 4-{5-[2-(4-Methyl-piperazin-1-yl)-4- oxo-4H-thiazol-5-ylidenemethyl]-indazol-1-ylmethyl}-3-trifluoromethyl- benzamide

21 5-[1-(4-Methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4- one

22 5-[1-(4-Hydroxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4- one

23 Methanesulfonic acid 4-{5-[2-(4- methyl-piperazin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-indazol-1- ylmethyl}-3-trifluoromethyl-phenylester

24 5-{1-[4-(2-Methoxy-ethoxy)-2- trifluoromethyl-benzyl]-1H-indazol-5-ylmethylene}-2-(4-methyl-piperazin- 1-yl)-thiazol-4-one

25 5-[1-(2,4-Dichloro-benzyl)-1H- indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one

26 5-[1-(4-Bromo-2-trifluoromethyl- benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4- one

27 5-[1-(4-Cyclopropyl-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4- one

28 5-[1-(2-Bromo-4-trifluoromethyl- benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4- one

29 5-[1-(2-Cyclopropyl-4-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4- one

30 5-[1-(4-lsopropenyl-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4- one

31 5-[1-(4-Cyclopropyl-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]- thiazol-4-one

32 2-(3R,4R-Dihydroxy-pyrrolidin-1-yl)-5-[1-(4-methoxy-2-trifluoromethyl- benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one

33 1-{5-[1-(4-Methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4- oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carboxylic acid

34 5-[1-(4-Methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2- piperazin-1-yl-thiazol-4-one

35 1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4- oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carboxylic acid

36 1-{5-[1-(4-Bromo-2-trifluoromethyl-benzyl)-1H-indazol-5-ylemthylene]-4- oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carboxylic acid

37 1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4- oxo-4,5-dihydro-thiazol-2-yl}-piperidine-3-(S)-carboxylic acid

38 1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4- oxo-4,5-dihydro-thiazol-2-yl}-piperidine-3-(R)-carboxylic acid

39 1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4- oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carboxylic acid

40 1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4- oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carboxylic acid

41 1-{5-[1-(4-Methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4- oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carboxylic acid

42 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4- methyl-[1,4]diazepan-1-yl)-thiazol-4-one

43 1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4- oxo-4,5-dihydro-thiazol-2-yl}-pyrrolidine-2-(R)-carboxylic acid

44 1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4- oxo-4,5-dihydro-thiazol-2-yl}-pyrrolidine-2-(S)-carboxylic acid

45 1-{5-[1-(4-Methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4- oxo-4,5-dihydro-thiazol-2-yl}-pyrrolidine-2-(R)-carboxylic acid

46 1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4- oxo-4,5-dihydro-thiazol-2-yl}-pyrrolidine-2-(R)-carboxylic acid

47 1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4- oxo-4,5-dihydro-thiazol-2-yl}-piperazine-2-(R)-carboxylic acid

48 1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4- oxo-4,5-dihydro-thiazol-2-yl}-piperidine-3-(S)-carboxylic acid

49 1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4- oxo-4,5-dihydro-thiazol-2-yl}-azetidine-2-(S)-carboxylic acid

50 1-{5-[1-(4-Methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4- oxo-4,5-dihydro-thiazol-2-yl}-azetidine-2-(S)-carboxylic acid

51 2-(3-(S)-Amino-piperidin-1-yl)-5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4- one

52 2-(3-(S)-Amino-piperidin-1-yl)-5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one

53 2-(3-(R)-Amino-piperidin-1-yl)-5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one

54 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2- [1,4]diazepan-1-yl-thiazol-4-one

55 5-[1-(2,4-Bis-trifluoromethyl-benzyl)- 1H-indazol-5-ylmethylene]-2-[1,4]diazepan-1-yl-thiazol-4-one

56 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-methoxy-ethyl)-piperazin-1-yl] thiazol-4-one

57 2-(4-Amino-piperidin-1-yl)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one

58 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2,2,2-trifluoro-ethyl)-piperazin-1- yl]-thiazol-4-one

59 2-(3-(R)-Amino-piperidin-1-yl)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4- one

60 2-(3-(S)-Amino-piperidin-1-yl)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4- one

61 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2,2-difluoro-ethyl)-piperazin-1-yl]- thiazol-4-one

62 2-(3-(R)-Amino-pyrrolidin-1-yl)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4- one

63 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-ethyl-piperazin-1-yl)-thiazol-4-one

64 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(S)-(2-pyrrolidin-1-ylmethyl-pyrrolidin- 1-yl)-thiazol-4-one

65 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2-(S),5-(S)-dimethyl-piperazin-1-yl)- thiazol-4-one

66 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2- methoxy-ethyl)-piperazin-1-yl]-thiazol-4-one

67 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-ethyl- piperazin-1-yl)-thiazol-4-one

68 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-hydroxy-azetidin-1-yl)-thiazol-4- one

69 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2S,5S-diaza-bicyclo[2.2.1]hept-2-yl)-thiazol- 4-one

70 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(5- methyl-2S,5S-diaza-bicyclo[2.2.1]hept-2-yl)-thiazol-4-one

71 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[5-(2- hydroxy-ethyl)-2S,5S-diaza-bicyclo[2.2.1]hept-2-yl]-thiazol-4-one

72 2-[4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4- oxo-4,5-dihydro-thiazol-2-yl}-piperazin-1-yl)-N,N-dimethyl- acetamide

73 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-ethoxy-ethyl)-piperazin-1-yl]-thiazol- 4-one

74 1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4- oxo-4,5-dihydro-thiazol-2-yl}-4-methyl-piperidine-4-carboxylic acid

75 1-{5-[1-{4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4- oxo-4,5-dihydro-thiazol-2-yl}-4-methyl-piperidine-4-carboxylic acid

76 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-hydroxy-ethyl)-[1,4]diazepan-1- yl]-thiazol-4-one

77 2-(3-Amino-azetidin-1-yl)-5-[1-(2,4- bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one

78 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2- (5-methyl-2S,5S-diaza-bicyclo[2.2.1]hept-2-yl)-thiazol-4-one

79 2-(4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4- oxo-4,5-dihydro-thiazol-2-yl}-piperazin-1-yl)-acetamide

80 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2- [5-(2-hydroxy-ethyl)-2S,5S-diaza-bicyclo[2.2.1]hept-2-yl]-thiazol-4-one

81 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-ethoxy-ethyl)-piperazin-1-yl]- thiazol-4-one

82 2-(4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4- oxo-4,5-dihydro-thiazol-2-yl}-piperazin-1-yl)-N-methyl-acetamide

83 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2-(R)-methyl-piperazin-1-yl)-thiazol- 4-one

84 2-(4-tert-Butyl-piperazin-1-yl)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one

85 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2- [5-(2-methoxy-ethyl)-2S,5S-diaza-bicyclo[2.2.1]hept-2-yl]-thiazol-4-one

86 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3- methyl-3,8-diaza-bicyclo[3.2.1]oct-8-yl)-thiazol-4-one

87 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-methyl-3,8-diaza-bicyclo[3.2.1]oct- 8-yl)-thiazol-4-one

88 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2- [4-(2-methoxy-acetyl)-cis-3,5-dimethyl-piperazin-1-yl]-thiazol-4-one

89 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2- [5-(2-methoxy-acetyl)-2S,5S-diaza-bicyclo[2.2.1]hept-2-yl]-thiazol-4-one

90 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2- [4-(2-methoxy-acetyl)-2-(R)-methyl-piperazin-1-yl]-thiazol-4-one

91 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-methoxy-acetyl)-piperazin-1-yl]- thiazol-4-one

92 2-(3-Amino-azetidin-1-yl)-5-[1-(4- chloro-2-cyclopropyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one

93 5-[1-(4-Chloro-2-cyclopropyl-benzyl)- 1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one

94 1-(5-[1-(4-Chloro-2-cyclopropyl- benzyl)-1H-indazol-5-ylmethylene]-4-oxo-dihydro-thiazol-2-yl)-azetidine-3- carboxylic acid

95 5-[1-(2-bromo-4-chlorobenzyl)-1H- indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one

96 5-[1-(4-Chloro-2-iodo-benzyl)-1H- indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one

97 5-[1-(2-Acetyl-4-chloro-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl- piperazin-1-yl)-thiazol-4-one

98 2-(3-Amino-azetidin-1-yl)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one

99 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2- (3R,4R-dihydroxy-pyrrolidin-1-yl)-thiazol-4-one

100 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2S,5S-diaza-bicyclo[2.2.1]hept-2-yl)- thiazol-4-one

101 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(8-methyl-3,8-diaza-bicyclo[3.2.1]oct- 3-yl)-thiazol-4-one

102 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2- (3-oxo-azetidin-1-yl)-thiazol-4-one

103 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(8- methyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-thiazol-4-one

104 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2- hydroxymethyl-piperazin-1-yl)-thiazol-4-one

105 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2- (2-hydroxymethyl-piperazin-1-yl)-thiazol-4-one

106 1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4- oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carboxylic acid amide

107 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4- isocyano-piperidin-1-yl)-thiazol-4-one

108 N-(1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4- oxo-4,5-dihydro-thiazol-2-yl}-piperidin-4-yl)-acetamide

109 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(1H-tetrazol-5-yl)-piperidin-1-yl]-thiazol-4- one

110 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(1H-tetrazol-5-yl)-piperidin-1-yl]- thiazol-4-one

111 N-(1-{5-[1-(4-Chloro-2- trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro- thiazol-2-yl}-piperidin-4-yl)-methanesulfonamide

112 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methoxy-piperidin-1-yl)-thiazol-4- one

113 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-methoxy-azetidin-1-yl)-thiazol-4- one

114 1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4- oxo-4,5-dihydro-thiazol-2-yl}-[1,4]diazepan-5-one

115 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2- (3-methylamino-pyrrolidin-1-yl)-thiazol-4-one

116 N-(1-{5-[1-(4-Chloro-2- trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro- thiazol-2-yl}-pyrrolidin-3-yl)-2,2,2-trifluoro-acetamide

117 (4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4- oxo-4,5-dihydro-thiazol-2-yl}-piperazin-1-yl)-acetic acid

118 1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4- oxo-4,5-dihydro-thiazol-2-yl}-[1,4]diazepan-5-one

119 (4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4- oxo-4,5-dihydro-thiazol-2-yl}-piperazin-1-yl)-acetic acid

120 N-(1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4- oxo-4,5-dihydro-thiazol-2-yl}-piperidin-4-yl)-methanesulfonamide

121 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-cyclopropyl-piperazin-1-yl)-thiazol- 4-one

122 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4- cyclopropyl-piperazin-1-yl)-thiazol-4-one

123 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-ethyl-piperazin-1-yl)-thiazol-4-one

124 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-ethyl- piperazin-1-yl)-thiazol-4-one

125 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2- (6-hydroxy-[1,4]diazepan-1-yl)-thiazol-4-one

126 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2- isoxazolidin-2-yl-thiazol-4-one

127 (4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4- oxo-4,5-dihydro-thiazol-2-yl}-piperazin-1-yl)-acetic acid ethyl ester

128 4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4- oxo-4,5-dihydro-thiazol-2-yl}-[1,4]diazepane-1-carboxylic acid ethyl ester

129 4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4- oxo-4,5-dihydro-thiazol-2-yl}-[1,4]diazepane-1-carboxylic acid ethyl ester

130 (1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4- oxo-4,5-dihydro-thiazol-2-yl}-piperidin-4-yloxy)-acetic acid methyl ester

131 (1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4- oxo-4,5-dihydro-thiazol-2-yl}-piperidin-4-yloxy)-acetic acid

132 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-(R)-hydroxymethyl-piperazin-1-yl)- thiazol-4-one

133 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-fluoro-ethyl)-[1,4]diazepan-1-yl]- thiazol-4-one

134 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2- (4-methanesulfonyl-[1,4]diazepan-1-yl)-thiazol-4-one

135 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2- [4-(2,2,2-trifluoro-ethyl)-[1,4]diazepan-1-yl]-thiazol-4-one

136 4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4- oxo-4,5-dihydro-thiazol-2-yl}-[1,4]diazepane-1-carboxylic acid 2,2,2-trifluoro-ethyl ester

137 1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4- oxo-4,5-dihydro-thiazol-2-yl}-pyrrolidine-3-carboxylic acid

138 2-[4-(2-Amino-acetyl)-[1,4]diazepan-1-yl]-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]- thiazol-4-one

139 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-(R)- hydroxymethyl-piperazin-1-yl)-thiazol-4-one

140 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-((2S)- hydroxymethyl-morpholin-4-yl)-thiazol-4-one

141 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3(R)- hydroxymethyl-morpholin-4-yl)-thiazol-4-one

142 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3(R)-hydroxymethyl-morpholin-4-yl)- thiazol-4-one

143 5-({1-[2,4-Bis(trifluoromethyl)benzyl}-1H-indazol-5-yl}methylidene)-2-[2(S)-(tert-butoxymethyl)morpholin-4-yl]- 1,3-thiazol-4(5H)-one

144 5-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4- oxo-4,5-dihydro-thiazol-2-yl}-hexahydro-furo[3,4-c]pyrrol-1-one

145 (1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4- oxo-4,5-dihydro-thiaol-2-yl}-pyrrolidin-3-yl)-acetic acid

146 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2- (1,1-dioxidothiomorpholin-4-yl)-thiazol-4-one

147 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(3,5-dimethyl-[1,2,4]triazol-4-yl)- piperidin-1-yl]-thiazol-4-one

148 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2- thiomorpholin-4-yl-thiazol-4-one

149 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-fluoro-azetidin-1-yl)-thiazol-4-one

150 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-tetrazol-1-yl-piperidin-1-yl)-thiazol- 4-one

151 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(6- hydroxy-[1,4]diazepan-1-yl)-thiazol-4-one

152 3-[(1-{5-[1-(4-Chloro-2- trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro- thiazol-2-yl}-azetidine-3-carbonyl)-amino]-propionic acid methyl ester

153 3-[(1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4- oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carbonyl)-amino]- propionic acid methyl ester

154 4-Amino-1-{5-[1-(4-chloro-2- trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro- thiazol-2-yl}-piperidine-4-carboxylicacid

155 N-(1-{5-[1-(4-Chloro-2- trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro- thiazol-2-yl}-piperidin-4-yl)-N-methyl-acetamide

156 4-Amino-1-{5-[1-(4-chloro-2- trifluoromethyl-benzyl)-1H-indazol-5ylmethylene]-4-oxo-4,5-dihydro- thiazol-2-yl}-piperidine-4-carboxylicacid ethyl ester

157 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-pyrazol-1-yl-piperidin-1-yl)-thiazol- 4-one

158 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-[1,2,4]triazol-1-yl-piperidin-1-yl)- thiazol-4-one

159 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2- (4-imidazol-1-yl-piperidin-1-yl)-thiazol-4-one

160 1-(1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4- oxo-4,5-dihydro-thiazol-2-yl}-piperidin-4-yl)-3-ethyl-urea

161 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-methylamino-azepan-1-yl)-thiazol- 4-one

162 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2- pyrrolidin-1-yl-thiazol-4-one

163 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2- (4-dimethylaminomethyl-4-hydroxy-piperidin-1-yl)-thiazol-4-one

164 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2- (4-hydroxy-4-imidazol-1-ylmethyl-piperidin-1-yl)-thiazol-4-one

165 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2- (3-ethyl-3-hydroxy-piperidin-1-yl)-thiazol-4-one

166 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-hydroxy-[1,4′]bipiperidinyl-1′-yl)- thiazol-4-one

167 8-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-1,3,8- triaza-spiro[4.5]decan-4-one

168 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[3-(2- hydroxy-ethyl)-4-methyl-piperazin-1-yl]-thiazol-4-one

169 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3,4- dihydro-1H-pyrrolo[1,2-a]pyrazin-2-yl)-thiazol-4-one

170 4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4- oxo-4,5-dihydro-thiazol-2-yl}-1,3-dimethyl-piperazin-2-one

171 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2- dimethylaminomethyl-morpholin-4-yl)-thiazol-4-one

172 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2(R)-(2- hydroxymethyl-morpholin-4-yl)-thiazol-4-one

173 Pyrrolidine-1-sulfonic acid (1-{5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H- indazol-5-ylmethylene]-4-oxo-4,5dihydro-thiazol-2-yl}-piperidine-4- carbonyl)-amide

174 Pyrrolidine-1-sulfonic acid (1-{5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H- indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4- carbonyl)-amide

175 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-iodo-1H-indazol-5-ylmethylene]- 2(S)-(2-hydroxymethyl-morpholin-4-yl)-thiazol-4-one

176 1-{5-[1-(4-Fluoro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4- oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carboxylic acid

177 5-[1-(4-Fluoro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2- ((2S)-2-hydroxymethyl-morpholin-4-yl)-thiazol-4-one

178 5-[1-(4-Fluoro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2- ((3R)-3-hydroxymethyl-piperazin-1-yl)-thiazol-4-one

179 5-[1-(2,4-Bis-trifluoromethyl- benzyl)-1H-indazol-5-ylmethylene]-2-(4,7-diaza-spiro[2.5]oct-7-yl)-thiazol-4- one

180 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-methyl-1H-indazol-5-ylmethylene]- 2-(2-(S)-hydroxymethyl-morpholin-4-yl)-thiazol-4-one

181 5-[1-(4-Chloro-2-trifluoromethyl- benzyl)-3-methyl-1H-indazol-5-ylmethylene]-2-(2-(S)-hydroxymethyl- morpholin-4-yl)-thiazol-4-one

182 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-methyl-1H-indazol-5-ylmethylene]- 2-(3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one

183 5-[1-(4-Chloro-2-trifluoromethyl- benzyl)-3-methyl-1H-indazol-5-ylmethylene]-2-(3-(R)-hydroxymethyl- piperazin-1-yl)-thiazol-4-one

184 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-chloro-1H-indazol-5-ylmethylene]- 2-(2-(S)-hydroxymethyl-morpholin-4-yl)-thiazol-4-one

185 5-[3-Chloro-1-(4-chloro-2- trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2-(S)-hydroxymethyl- morpholin-4-yl)-thiazol-4-one

186 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-chloro-1H-indazol-5-ylmethylene]- 2-(3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one

187 5-[3-Chloro-1-(4-chloro-2- trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-(R)-hydroxymethyl- piperazin-1-yl)-thiazol-4-one

188 4-[5-({1-[2,4- Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]morpholine- 2-carboxylic acid

189 1-{5-({1-[4-Chloro-2- (trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-4-(S)-fluoro-L-proline

190 Methyl 1-[5-({1-[2,4- bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]piperidine-4- carboxylate

191 1-[5-({1-[2,4- Bis(trifluoromethyl)benzyl]-3-iodo-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]piperidine-4- carboxylic acid

192 5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(2- (R)-4,dimethylpiperazin-1-yl)-1,3-thiazol-4(5H)-one

193 5-({1-[4-Chloro-2- (trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(2-(R),4- dimethylpiperazin-1-yl)-1,3-thiazol-4(5H)-one

194 4-[5-({1-[4-Chloro-2- (trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro- 1,3-thiazol-2-yl]morpholine-3-(R)-carboxylic acid

195 5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3- (R)-(hydroxymethyl)-4-methylpiperazin-1-yl]-1,3-thiazol- 4(5H)-one

196 5-({1-[4-Chloro-2- (trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3-(R)- (hydroxymethyl)-4-methylpiperazin-1-yl]-1,3-thiazol-4(5H)-one

197 5-({1-[4-Chloro-2- (trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(3-hydroxy-4,7- dihydroisoxazolo[5,4-c]pyridin-6(5H)-yl)-1,3-thiazol-4(5H)-one

198 1-{5-({1-[4-Chloro-2- (trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro- 1,3-thiazol-2-yl]-1,2,3,6-tetrahydropyridine-4-carboxylic acid

199 5-({1-[4-Chloro-2- (trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[4-(2- methoxyethyl)-2-(R)-methylpiperazin-1-yl]-1,3-thiazol-4(5H)-one

200 5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3- (S)-(hydroxymethyl)piperazin-1-yl]-1,3-thiazol-4(5H)-one

201 2-[2-(Aminomethyl)morpholin-4-yl]-5-({1-[2,4-bis(trifluoromethyl)benzyl]- 1H-indazol-5-yl}methylidene)-1,3-thiazol-4(5H)-one

202 5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3- (2,6-cis-dimethylmorpholin-4-yl)azetidin-1-yl]-1,3-thiazol-4(5H)-one

203 5-({1-[4-Chloro-2- (trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3-(2,6-cis- dimethylmorpholin-4-yl)azetidin-1-yl]-1,3-thiazol-4(5H)-one

204 5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(3- morpholin-4-ylazetidin-1-yl)-1,3-thiazol-4(5H)-one

205 5-({1-[4-Chloro-2- (trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(3-morpholin-4- ylazetidin-1-yl)-1,3-thiazol-4(5H)-one

206 5-({1-[4-Chloro-2- (trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3-(S)- (hydroxymethyl)piperazin-1-yl]-1,3-thiazol-4(5H)-one

207 5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[4- tert-butyl-3-(R)-(hydroxymethyl)piperazin-1-yl]-1,3- thiazol-4(5H)-one

208 5-({1-[4-Chloro-2- (trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3-(R)- (methoxymethyl)piperazin-1-yl]-1,3-thiazol-4(5H)-one

209 5-({1-[4-Chloro-2- (trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3-(S)- (methoxymethyl)piperazin-1-yl]-1,3-thiazol-4(5H)-one

210 5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3- (R)-(methoxymethyl)piperazin-1-yl]-1,3-thiazol-4(5H)-one

211 5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3- (S)-(methoxymethyl)piperazin-1-yl]-1,3-thiazol-4(5H)-one

212 5-({1-[4-Chloro-2- (trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[2-(S)- (hydroxymethyl)morpholin-4-yl]-1,3-thiazol-4(5H)-one

213 Methyl {1-[5-({1-[2,4- bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5- dihydro-1,3-thiazol-2-yl]-5-(R)-(hydroxymethyl)pyrrolidin-3-(R)- yl}carbamate

214 (1R,6R)-7-[5-({1-[2,4- Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-4-oxa-2,7- diazabicyclo[4.2.1]nonan-3-one

215 5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[4- (cyclopropylcarbonyl)-3-(R)-(hydroxymethyl)piperazin-1-yl]-1,3- thiazol-4(5H)-one

216 Methyl 4-[5-({1-[2,4- bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5- dihydro-1,3-thiazol-2-yl]-2-(R)-(hydroxymethyl)piperazine-1- carboxylate

217 1-[2,4-Bis(trifluoromethyl)benzyl]-5-({2-[3-(R)-(hydroxymethyl)piperazin- 1-yl]-4-oxo-1,3-thiazol-5(4H)-ylidene}methyl)-1H-indazole-3- carbonitrile

218 1-[2,4-Bis(trifluoromethyl)benzyl]-5-({2-[3-(S)-(hydroxymethyl)piperazin- 1-yl]-4-oxo-1,3-thiazol-5(4H)-ylidene}methyl)-1H-indazole-3- carbonitrile

219 5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2- (3,3,4-trimethylpiperazin-1-yl)-1,3-thiazol-4(5H)-one

220 4-[5-({1-[2,4- Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5- dihydro-1,3-thiazol-2-yl]-N-tert-butylpiperazine-2-(S)-carboxamide

221 5-({1-[4-Chloro-2- (trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(3,3,4- trimethylpiperazin-1-yl)-1,3-thiazol-4(5H)-one

222 1-[4-Chloro-2- (trifluoromethyl)benzyl]-5-{[4-oxo-2-(3,3,4-trimethylpiperazin-1-yl)-1,3- thiazol-5(4H)-ylidene]methyl]-1H-indazole-3-carbonitrile

223 1-[4-Chloro-2- (trifluoromethyl)benzyl]-5-{[2-(4-methylpiperazin-1-yl)-4-oxo-1,3- thiazol-5(4H)-ylidene]methyl]-1H-indazole-3-carbonitrile

224 1-[4-Chloro-2- (trifluoromethyl)benzyl]-5-({2-[4-(cyclopropylmethyl)piperazin-1-yl]-4- oxo-1,3-thiazol-5(4H)-ylidene}methyl)-1H-indazole-3- carbonitrile

225 5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2- [(3S,4S)-3-hydroxy-4-morpholin-4-ylpyrrolidin-1-yl]-1,3-thiazol-4(5H)- one

226 (2R)-4-[5-({1-[4-Chloro-2- (trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro- 1,3-thiazol-2-yl]-N-methylpiperazine-2-carboxamide

227 (2R)-4-[5-({1-[2,4- Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5- (dihydro-1,3-thiazol-2-yl]-N-methylpiperazine-2-carboxamide

228 (2S)-N-tert-Butyl-4-[5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro- 1,3-thiazol-2-yl]piperazine-2-carboxamide

229 5-({1-[2-Chloro-4-(1-hydroxy-1- methylethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3-(R)- (hydroxymethyl)piperazin-1-yl]-1,3-thiazol-4(5H)-one

230 5-({1-[2-Chloro-4-(1- methylethenyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3-(R) (hydroxymethyl)piperazin-1-yl]-1,3-thiazol-4(5H)-one

231 5-({1-[2-Chloro-4-(1-hydroxy-1- methylethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[2-(R)- (hydroxymethyl)morpholin-4-yl]-1,3-thiazol-4(5H)-one

232 5-({1-[2-Chloro-4-(1-hydroxy-1- methylethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(4-methylpiperazin- 1-yl)-1,3-thiazol-4(5H)-one

233 5-({1-[2-Chloro-4-(1-hydroxy-1- methylethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(3,5-(cis)- dimethylpiperazin-1-yl)-1,3-thiazol-4(5H)-one

234 5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[2- (S)-(methoxymethyl)morpholin-4-yl]-1,3-thiazol-4(5H)-one

235 5-({1-[4-Chloro-2- (trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[2-(S)- (methoxymethyl)morpholin-4-yl]-1,3-thiazol-4(5H)-one

236 5-({1-[4-Hydroxy-2- (trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[2(S)- (methoxymethyl)morpholin-4-yl]-1,3-thiazol-4(5H)-one

237 5-({1-[4-Bromo-2- (trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[2-(R)- (hydroxymethyl)morpholin-4-yl]-1,3-thiazol-4(5H)-one

238 5-({1-[2,4-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(3,5- (cis)-dimethylpiperazin-1-yl)-1,3-thiazol-4(5H)-one

239 5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-((3R, 5S)-3,4,5-trimethylpiperazin-1-yl)-1,3-thiazol-4(5H)-one

240 (2R,6S)-4-[5-({1-[2,4- Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5- dihydro-1,3-thiazol-2-yl]-1,1,2,6-tetramethylpiperazin-1-ium chloride

241 5-({1-[4-Chloro-2- (trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-((3R,5S)-3,5- dimethylpiperazin-1-yl)-1,3-thiazol-4(5H)-one

242 5-({1-[4-(1-Hydroxy-1-methylethyl)-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(4-methylpiperazin- 1-yl)-1,3-thiazol-4(5H)-one

243 2-((3R,5S)-3,5-Dimethylpiperazin-1- yl)-5-({1-[4-(1-hydroxy-1-methylethyl)-2- (trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazol-4(5H)-one

244 5-({1-[4-(1-Hydroxy-1-methylethyl)-2-(trifluoromethyl)benzyl]-1H-indazol-5- yl}methylidene)-2-[2-(S)-(hydroxymethyl)morpholin-4-yl]-1,3- thiazol-4(5H)-one

245 4-[(5Z)-5-({1-[4-(1-Hydroxy-1- methylethyl)-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro- 1,3-thiazol-2-yl]piperazine-1-carboxylic acid

246 5-({1-[4-(1-Hydroxy-1-methylethyl)-2-(trifluoromethyl)benzyl]-1H-indazol-5- yl}methylidene)-2-[3-(R)-(hydroxymethyl)piperazin-1-yl]-1,3- thiazol-4(5H)-one

247 2-[3-(R)-(Hydroxymethyl)piperazin-1-yl]-5-({1-[4-(1-methylethenyl)-2- (trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazol-4(5H)-one

248 2-[3-(R)-(Hydroxymethyl)piperazin-1- yl]-5-({1-[4-methoxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazol-4(5H)-one

249 2-[(2R)-2-(Hydroxmethyl)morpholin- 4-yl]-5-({1-[4-hydroxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazol-4(5H)-one

250 2-[(3R)-3-(Hydroxymethyl)piperazin- 1-yl]-5-({1-[4-hydroxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazol-4(5H)-one

251 (5Z)-2-[(2S)-2- (Hydroxymethyl)morpholin-4-yl]-5- ({1-[4-hydroxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazol-4(5H)-one

252 5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-1,3- thiazol-4(5H)-one

253 5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[(2R)-2-(hydroxymethyl)-4-methylpiperazin- 1-yl]-1,3-thiazol-4(5H)-one

254 5-({1-[4-Chloro-2- (trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[(2R)-2- (hydroxymethyl)-4-methylpiperazin-1-yl]-1,3-thiazol-4(5H)-one

255 5-({1-[4-Chloro-2- (trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-((2S)-2- ethylpiperazin-1-yl)-1,3-thiazol-4(5H)- one

256 5-({1-[4-Chloro-2- (trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-24(2S)-2-ethyl-4- methylpiperazin-1-yl)-1,3-thiazol-4(5H)-one

257 2-[(2R,4R)-4-Amino-2- (hydroxymethyl)pyrrolidin-1-yl]-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]- 1H-indazol-5-yl}methylidene)-1,3-thiazol-4(5H)-one

258 2-[(2R,4R)-4-Amino-2- (hydroxymethyl)pyrrolidin-1-yl]-5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazol- 4(5H)-one

259 N-{1-[(3R,5R)-5-({1-[2,4- Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5- dihydro-1,3-thiazol-2-yl]-5-(hydroxymethyl)pyrrolidin-3- yl}acetamide

260 N-{(3R,5R)-1-[5-({1-[2,4- Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5- dihydro-1,3-thiazol-2-yl]-5-(hydroxymethyl)pyrrolidin-3- yl}cyclopropanecarboxamide

261 N-{(3R,5R)-1-[5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro- 1,3-thiazol-2-yl]-5-(hydroxymethyl)pyrrolidin-3- yl}acetamide

262 N-{(2R,4R)-1-[2,4- Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-{2- (hydroxymethyl)-4-[(1-methylethyl)amino]pyrrolidin-1-yl}- 1,3-thiazol-4(5H)-one

263 N-{(2R,4R)-1-[4-Chloro-2- (trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-{2- (hydroxymethyl)-4-[(1-methylethyl)amino]pyrrolidin-1-yl}- 1,3-thiazol-4(5H)-one

264 N-2-{(3S)-1-{5-({1-[2,4- Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]pyrrolidin-3- yl}alaninamide

265 N-2-{(3S)-1-[5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]pyrrolidin-3-yl}alaninamide

266 5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-{(3S)-3-[(2,2-difluoroethyl)amino]piperidin- 1-yl}-1,3-thiazol-4(5H)-one

267 5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-{3- [(2-hydroxyethyl)amino]piperidin-1-yl}-1,3-thiazol-4(5H)-one

268 1-[5-({1-[4-Chloro-2- (trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-4-hydroxypiperidine- 4-carboxylic acid

269 1-[5-({1-[2,4- Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5- dihydro-1,3-thiazol-2-yl]-4-hydroxypiperidine-4-carboxylic acid

270 5-({1-[4-Chloro-2- (trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3- (methylamino)azetidin-1-yl]-1,3- thiazol-4(5H)-one

271 4-[5-({1-[4-Chloro-2- (trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene-4-oxo-4,5-dihydro- 1,3-thiazol-2-yl]-N-methoxypiperazine-2-carboxamide

272 4-[5-({1-[2,4- Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5- dihydro-1,3-thiazol-2-yl]-N-methoxypiperazine-2-carboxamide

273 4-[(5Z)-5-({1-[4-Chloro-2- (trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro- 1,3-thiazol-2-yl]piperazine-2-carboxamide

274 4-[(5Z)-5-({1-[2,4- Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]piperazine-2- carboxamide

275 2-[(2R)-2-(Hydroxymethyl)morpholin-4-yl]-5-({1-[4-(1-methylethenyl)-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazol-4(5H)-one

276 1-[5-({1-[4-Chloro-2- (trifluoromethyl)benzyl]-3-methyl-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]piperidine-4- carboxylic acid

277 5-({1-[4-Chloro-2- (trifluoromethyl)benzyl]-3-methyl-1H-indazol-5-yl}methylidene)-2-[(3S)-3- (hydroxymethyl)piperazin-1-yl]-1,3-thiazol-4(5H)-one

278 5-({1-[4-Chloro-2- (trifluoromethyl)benzyl]-3-methyl-1H-indazol-5-yl}methylidene)-2-(3,3,4-trimethylpiperazin-1-yl)-1,3-thiazol- 4(5H)-one

279 tert-Butyl (2R)-4-[5-({1-[2,4-bis(trifluoromethyl)benzyl]-3-iodo-1H-indazol-5-yl}methylidene)-4-oxo-4,5- dihydro-1,3-thiazol-2-yl]-2-(hydroxymethyl)piperazine-1- carboxylate

280 {(2S)-4-[5-({1-[2,4- Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]morpholin-2- yl}methyl acetate

281 2-[(2S)-2-(Hydroxymethyl)morpholin-4-yl]-5-[(1-{[3-(trifluoromethyl)pyridin- 2-yl]methyl}-1H-indazol-5-yl)methylidene]-1,3-thiazol-4(5H)-one

282 Methyl N-({(2S)-4-[5-({1-[2,4- bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]morpholin-2- yl}carbonyl)glycinate

283 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-(S)- hydroxymethyl-piperazin-1-yl)-thiazol-4-oneC) Synthesis

The invention provides methods of making the disclosed compoundsaccording to traditional organic synthetic methods as well as matrix orcombinatorial synthetic methods. Schemes 1 to 5 describe suggestedsynthetic routes. Using the scheme, the guidelines below, and theexamples, a person of skill in the art may develop analogous or similarmethods for a given compound that is within the invention. These methodsare representative of the synthetic schemes, but are not to be construedas limiting the scope of the invention.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. Where the processes for the preparation of the compoundsaccording to the invention give rise to mixtures of stereoisomers, theseisomers may be separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form or asindividual enantiomers or diasteromers by either stereospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers or diastereomers by standardtechniques, such as the formation of stereoisomeric pairs by saltformation with an optically active base, followed by fractionalcrystallization and regeneration of the free acid. The compounds mayalso be resolved by formation of stereoisomeric esters or amides,followed by chromatographic separation and removal of the chiralauxiliary. Alternatively, the compounds may be resolved using a chiralHPLC column. It is to be understood that all stereoisomers, racemicmixtures, diastereomers, geometric isomers, and enantiomers thereof areencompassed within the scope of the present invention.

Furthermore, some of the crystalline forms for the compounds may existas polymorphs and as such are intended to be included in the presentinvention. In addition, some of the compounds may form solvates withwater (i.e., hydrates) or common organic solvents, and such solvates arealso intended to be encompassed within the scope of this invention.

Examples of the described synthetic routes include Schemes 1-5, Examples1 through 283, and General Procedures A-I. Compounds analogous to thetarget compounds of these examples can be made according to similarroutes. The disclosed compounds are useful as pharmaceutical agents asdescribed herein.

Abbreviations or acronyms useful herein include:

-   AIBN (2,2′-Azobisisobutyronitrile)-   Boc (tert butyl carbamate)-   BOP (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium    hexyluorophosphate)-   BuLi (butyllithium)-   DIBAL-H (Diisobutylaluminum hydride)-   DCM (Dichloromethane)-   DIEA (Diisopropylethylamine)-   DMAP (4-(dimethylamino)pyridine)-   DME (Ethylene glycol dimethyl ether)-   DMF (dimethylformamide)-   DMPU (1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone)-   DMSO (methyl sulfoxide)-   EDC(N—(3-Dimethylaminopropyl)-N′-ethylcarbodiimide)-   EDCI (1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride)-   Et (ethyl)-   EtOAc (ethyl acetate)-   h or hr (hour(s))-   HATU (O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate)-   HCl (Hydrochloric acid)-   HMPA (Hexamethylphosphoramide)-   HOBt (1-Hydroxybenzotriazole monohydrate)-   HPLC (High Performance Liquid Chromatography)-   LCMS (high pressure liquid chroatography with mass spectrometer)-   LDA (Lithium diisopropylamide)-   LHMDS (lithium hexamethyl disilazide)-   Me (methyl)-   MeCN (acetonitrile)-   MeOH (methyl alcohol)-   Mg (milligram)-   MOM (Methoxymethyl)-   NaHMDS (sodium hexamethyl disilazide)-   NaO^(t)Bu (sodium tert-butoxide)-   NBS (N-Bromosuccinimide)-   NMP (N-Methyl Pyrrolidinone)-   N,N-DMA (N,N-dimethylacetamide)-   rt or RT (room temperature)-   SPE (solid phase extraction)-   TBTU (O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium    hexafluorophosphate)-   tBu (tert-butyl)-   TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy, free radical)-   TFA (trifluoroacetic acid);-   THF (tetrahydrofuran)-   TLC (thin layer chromatography)    General Guidance

The compounds of Formula (I), wherein X, R₁, R₂, R₃ and

are defined as in Formula I, may be synthesized as outlined by thegeneral synthetic route illustrated in Scheme 1. Treatment of anappropriate 1H-Indazole-5-carbaldehyde II and an appropriate substitutedbenzyl or an appropriate substituted alkylheteroaryl (C₁alkylaryl) III,a known compound or compound prepared by known methods, wherein Y is asuitably selected leaving group such as Cl, Br, I, tosylate, mesylate,and the like, both of which are either commercially available or can bemade from commercially available starting materials, with a base such asK₂CO₃, Cs₂CO₃, NaH, and the like, in a solvent such as NMP, DMF, THF,and the like, at a temperature preferably between 25-150° C. can providethe substituted 1-Benzyl-1H-indazole-5-carbaldehyde IV. Knoevenagelreaction of aldehyde IV with a suitably compound of formula V in thepresence of a catalytic amount of base such as piperidine and an acidsuch as benzoic acid can provide compound VI. Alternatively, theKnoevenagel reaction of aldehyde IV with a suitable compound of formulaV in the presence of DBU can provide compound VI. The Knoevenagelreaction is typically performed in an aprotic solvent such as toluene ata temperature preferably between 100-200° C. The reaction betweenaldehyde IV and rhodanine V may also be performed with a base such assodium acetate in a solvent such as acetonitrile at a temperaturepreferably between 50-150° C., or in the presence of ammonium acetate inacetic acid at a temperature preferably between 50-150° C. The compoundof formula VI is reacted with a compound of formula R_(a)Y, a knowncompound or compound prepared by known methods, wherein R_(a) is asuitably selected alkyl such as methyl, ethyl, isopropyl, and the like,and Y, a suitably selected leaving group such as Cl, Br, I, tosylate,mesylate, and the like, in the presence of a base such as K₂CO₃, Et₃N,DIEA, and the like, in an organic solvent such as MeOH, MeCN, DCM, THF,and the like, at a temperature preferably between 25-80° C., to yieldthe corresponding compound of formula VII.

Treatment of VII with an appropriate amine

in a solvent such as acetonitrile, MeOH, DMF, and the like, at atemperature preferably between 25-180° C. can provide compounds ofFormula (I).

In the case where the cyclic amine of formula

incorporates another protected nitrogen such as Boc, Cbz, and the like,this nitrogen may be deprotected under appropriate conditions known tothose skilled in the art to afford a compound of formula I of thepresent invention. For example, Boc-protected amines may be deprotectedunder acidic conditions using reagents such as HCl, TFA, and the like.Likewise, Cbz-protected amines may be deprotected under acidicconditions or hydrogenolysis.

The compounds of Formula (I), wherein X, R₁, R₂, R₃ and

are defined as in Formula I, may alternatively be synthesized asoutlined by the general synthetic route illustrated in Scheme 2.Accordingly, a suitable compound of formula V, a known compound orcompound prepared by known methods, is reacted with a compound offormula R_(a)Y, a known compound or compound prepared by known methods,wherein R_(a) is a suitably selected alkyl such as methyl, ethyl,isopropyl, and the like, and Y, a suitably selected leaving group suchas Cl, Br, I, tosylate, mesylate, and the like, in the presence of abase such as K₂CO₃, Et₃N, DIPEA, and the like, in an organic solventsuch as MeOH, DCM, THF, and the like, at a temperature preferablybetween 25-80° C., to yield the corresponding compound of formula VIII.Treatment of VIII with an appropriate amine

in a solvent such as acetonitrile, MeOH, DMF, and the like, at atemperature preferably between 25-150° C. can provide compounds ofFormula IX. Knoevenagel reaction of aldehyde IV with a suitably compoundof formula IX in the presence of a catalytic amount of base such aspiperidine and an acid such as benzoic acid can provide compounds ofFormula (I). Alternatively, the Knoevenagel reaction of aldehyde IV witha suitable compound of formula IX in the presence of DBU can providecompound of formula (I). The Knoevenagel reaction is typically performedin an aprotic solvent such as toluene at a temperature preferablybetween 100-200° C. The reaction between aldehyde IV and a suitablycompound of formula IX may also be performed with a base such as sodiumacetate in a solvent such as acetonitrile at a temperature preferablybetween 50-150° C., or in the presence of ammonium acetate in aceticacid at a temperature preferably between 50-150° C.

In the case where the cyclic amine of formula

incorporates another protected nitrogen such as Boc, Cbz, and the like,this nitrogen may be deprotected under appropriate conditions known tothose skilled in the art to afford a compound of formula I of thepresent invention. For example, Boc-protected amines may be deprotectedunder acidic conditions using reagents such as HCl, TFA, and the like.Likewise, Cbz-protected amines may be deprotected under acidicconditions or hydrogenolysis.

The compounds of Formula (I), wherein X, R₁, R₂, R₃ and

are defined as in Formula I, may alternatively be synthesized asoutlined by the general synthetic route illustrated in Scheme 3.Accordingly, a suitable compound of formula X, prepared as described inScheme 1, wherein X, R₁, R₃ and

are defined as in Formula I and wherein Z is a suitably selected leavinggroup such as Cl, Br, I, triflate, mesylate, and the like, is reactedwith a compound of formula XI, wherein R₂ is defined as in Formula I andW a suitably selected boronic acid, boronic ester, tin derivative, andthe like, which are either commercially available or can be made fromcommercially available starting materials, in the presence of atransition metal catalyst such as Pd(OAc)₂, Pd(Ph₃P)₄, Pd(dppf)Cl₂,Pd₂(dba)₃ and the like, in the presence of a base, such as K₂CO₃,Cs₂CO₃, potassium phosphate, and the like, in the presence of a ligand,such as PPh₃, tricyclohexylphosphine, tri-t-butylphosphine,biphenyl-2-yl-di-t-butyl-phosphane, and the like, in an organic solventsuch as toluene, dioxane, THF, EtOH, water, and the like, at atemperature in the range of from about 20° C. to about 180° C., to yieldthe corresponding compound of formula I.

The compounds of Formula (I), wherein X, R₁, R₂, R₃ and

are defined as in Formula I, may alternatively be synthesized asoutlined by the general synthetic route illustrated in Scheme 4.Accordingly, a suitable compound of formula XII, prepared as describedin Scheme 1, wherein X, R₂, R₃ and

are defined as in Formula I and wherein Z is a suitably selected leavinggroup such as Cl, Br, I, triflate, mesylate, and the like, is reactedwith a compound of formula XIII, wherein R₁ is defined as in Formula Iand W a suitably selected boronic acid, boronic ester, tin derivative,and the like, which are either commercially available or can be madefrom commercially available starting materials, in the presence of atransition metal catalyst such as Pd(OAc)₂, Pd(Ph₃P)₄, Pd(dppf)Cl₂,Pd₂(dba)₃ and the like, in the presence of a base, such as K₂CO₃,Cs₂CO₃, potassium phosphate, and the like, in the presence of a ligand,such as PPh₃, tricyclohexylphosphine, tri-t-butylphosphine,biphenyl-2-yl-di-t-butyl-phosphane, and the like, in an organic solventsuch as toluene, dioxane, THF, EtOH, water, and the like, at atemperature in the range of from about 20° C. to about 180° C., to yieldthe corresponding compound of formula I.

The compounds of Formula (I), wherein X, R₁, R₂, R₃ and

are defined as in Formula I, may be synthesized as outlined by thegeneral synthetic route illustrated in Scheme 5. Treatment of anappropriate 1H-Indazole-5-carbaldehyde II and an appropriate substitutedbenzyl or an appropriate substituted alkylheteroaryl (C₁alkylaryl) XIV,a known compound or compound prepared by known methods, wherein Y is asuitably selected leaving group such as Cl, Br, I, tosylate, mesylate,and the like, and wherein Z is a suitably selected leaving group such asCl, Br, I, tosylate, and the like, both of which are either commerciallyavailable or can be made from commercially available starting materials,with a base such as K₂CO₃, Cs₂CO₃, NaH, and the like, in a solvent suchas NMP, DMF, THF, and the like, at a temperature preferably between25-150° C. can provide the substituted1-Benzyl-1H-indazole-5-carbaldehyde or the substituted1-Pyridin-2-ylmethyl-1H-indazole-5-carbaldehyde XV.

Accordingly, a suitable compound of formula XV is reacted with acompound of formula XIII, wherein R₁ is defined as in Formula I and W asuitably selected boronic acid, boronic ester, tin derivative, and thelike, f which are either commercially available or can be made fromcommercially available starting materials, in the presence of atransition metal catalyst such as Pd(OAc)₂, Pd(Ph₃P)₄, Pd(dppf)Cl₂,Pd₂(dba)₃ and the like, in the presence of a base, such as K₂CO₃,Cs₂CO₃, potassium phosphate, and the like, in the presence of a ligand,such as PPh₃, tricyclohexylphosphine, tri-t-butylphosphine,biphenyl-2-yl-di-t-butyl-phosphane, and the like, in an organic solventsuch as toluene, dioxane, THF, EtOH, water, and the like, at atemperature in the range of from about 20° C. to about 180° C., to yieldthe corresponding compound of formula IV. Aldehyde IV can be transformedto provide compounds of Formula (I) as described in Scheme 1.

EXAMPLES

General Procedure A: A solution of 1H-Indazole-5-carbaldehyde (7.6 g,52.0 mmol) and an appropriate substituted benzyl bromide (62.1 mmol) inDMF (120 mL) was treated with Cs₂CO₃ (17 g, 52.1 mmol), and the mixturewas heated in an oil bath at 100° C. for 16 h. The reaction was cooledto RT and partitioned between EtOAc and H₂O. The organic phase waswashed with water (3×), brine, dried over Na₂SO₄ and concentrated invacuo. Silica gel chromatography (EtOAc/hexanes) afforded the desiredisomer. Recrystallization of the desired isomer from EtOAc/Hexanesafforded the desired pure aldehyde isomer.

General Procedure B:

2-thioxo-thiazolidin-4-one (0.59 g, 4.42 mmol) and aldehyde fromProcedure A (4.42 mmol) were dissolved in toluene (40 mL) and treatedwith benzoic acid (0.22 mmol) and piperidine (0.22 mmol). The flask wasequipped with a Dean-Stark trap, and the reaction was refluxed at 130°C. using an oil bath for 16 h. After cooling to RT, the product wascollected by filtration and washed with toluene and water to afford thedesired pure5-[1-(substituted-benzyl)-1H-indazol-5-ylmethylene]-2-thioxo-thiazolidin-4-oneproduct.

A mixture of5-[1-(substituted-benzyl)-1H-indazol-5-ylmethylene]-2-thioxo-thiazolidin-4-one(0.32 mmol) and DIEA (0.63 mmol) in DCM (5 mL) was treated with anappropriate iodoalkane (1 mmol). The reaction mixture was stirred at RTfor 16 h and partitioned between DCM and H₂O. The organic phase waswashed with brine, dried over Na₂SO₄ and concentrated in vacuo to affordthe desired pure5-[1-(substituted-benzyl)-1H-indazol-5-ylmethylene]-2-alkylsulfanyl-thiazol-4-oneproduct.

To a mixture of5-[1-(substituted-benzyl)-1H-indazol-5-ylmethylene]-2-alkylsulfanyl-thiazol-4-one(0.31 mmol) and the appropriate cyclic amine (0.37 mmol) was addedMeOH/DCM (2:1 v/v, 8 mL). The suspension was heated at 70° C. underreflux conditions for 4 h. The reaction was cooled to RT and the solventconcentrated in vacuo. Silica gel chromatography or reverse phase HPLCafforded the desired pure product.

General Procedure C:

To a mixture of 2-thioxo-thiazolidin-4-one (0.35 mmol) and aldehyde fromProcedure A (0.32 mmol) was added acetic acid (2.0 mL) and NH₄OAc (0.95mmol). The suspension was heated at 95° C. (aluminum heating block) for2 h. The product was collected by filtration, washed with cold ethanoland triturated with EtOAc/hexanes to afford the desired pure5-[1-(substituted-benzyl)-1H-indazol-5-ylmethylene]-2-thioxo-thiazolidin-4-oneproduct.

A mixture of5-[1-(substituted-benzyl)-1H-indazol-5-ylmethylene]-2-thioxo-thiazolidin-4-one(0.32 mmol) and DIEA (0.63 mmol) in DCM (5 mL) was treated with anappropriate iodoalkane (1 mmol). The reaction mixture was stirred at RTfor 16 h and partitioned between DCM and H₂O. The organic phase waswashed with brine, dried over Na₂SO₄ and concentrated in vacuo to affordthe desired pure5-[1-(substituted-benzyl)-1H-indazol-5-ylmethylene]-2-alkylsulfanyl-thiazol-4-oneproduct.

To a mixture of5-[1-(substituted-benzyl)-1H-indazol-5-ylmethylene]-2-alkylsulfanyl-thiazol-4-one(0.31 mmol) and the appropriate cyclic amine (0.37 mmol) was addedMeOH/DCM (2:1 v/v, 8 mL). The suspension was heated at 70° C. underreflux conditions for 4 h. The reaction was cooled to RT and the solventconcentrated in vacuo. Silica gel chromatography or reverse phase HPLCafforded the desired pure product.

General Procedure D:

2-thioxo-thiazolidin-4-one (10 g, 75 mmol) in aqueous 2% NaOH (200 mL)was treated with the appropriate iodoalkane (82.5 mmol). The reactionmixture was stirred at RT for 16 h and partitioned between DCM and H₂O.The organic phase was washed with a cold saturated NaHCO₃ solution, H₂O,dried over Na₂SO₄ and concentrated in vacuo to afford the desired pure2-alkylsulfanyl-thiazol-4-one product.

To a mixture of 2-alkylsulfanyl-thiazol-4-one (2.71 mmol) and theappropriate cyclic amine (2.71 mmol) was added EtOH (15 mL). Thesuspension was heated at 65° C. for 16 h. The reaction was cooled to RTand the solvent concentrated in vacuo. Silica gel chromatography(MeOH/DCM) afforded the desired pure 2-cyclic amino-thiazol-4-oneproduct.

2-Cyclic amino-thiazol-4-one (1.33 mmol) and the aldehyde from ProcedureA (1.33 mmol) were dissolved in toluene (16 mL) and treated with benzoicacid

(0.07 mmol) and piperidine (0.07 mmol). The flask was equipped with aDean-Stark trap, and the reaction was refluxed at 130° C. using an oilbath for 12 h. After cooling to RT, the product was collected byfiltration and triturated with hexanes to afford the desired pureproduct.

General Procedure E:

2-thioxo-thiazolidin-4-one (10 g, 75 mmol) in aqueous 2% NaOH (200 mL)was treated with the appropriate iodoalkane (82.5 mmol). The reactionmixture was stirred at RT for 16 h and partitioned between DCM and H₂O.The organic phase was washed with a cold saturated NaHCO₃ solution, H₂O,dried over Na₂SO₄ and concentrated in vacuo to afford the desired pure2-alkylsulfanyl-thiazol-4-one product.

To a mixture of 2-alkylsulfanyl-thiazol-4-one (2.71 mmol) and theappropriate cyclic amine (2.71 mmol) was added EtOH (15 mL). Thesuspension was heated at 65° C. for 16 h. The reaction was cooled to RTand the solvent concentrated in vacuo. Silica gel chromatography(MeOH/DCM) or reverse phase HPLC afforded the desired pure 2-cyclicamino-thiazol-4-one product.

To a mixture of 2-cyclic amino-thiazol-4-one (0.18 mmol) and aldehydefrom Procedure A (0.18 mmol) was added acetic acid (1.0 mL) and NH₄OAc(0.1 mmol). The suspension was heated at 100° C. (aluminum heatingblock) for 16 h and then diluted with water. The product was collectedby filtration and purified using Silica gel chromatography or reversephase HPLC to afford the desired pure product.

General Procedure F:

To a solution of an appropriate5-[1-(4-bromo-2-substituted-benzyl)-1H-indazol-5-ylmethylene]-2-(cyclicamino)-thiazol-4-one (0.053 mmol), an appropriate substituted boronicacid (0.074 mmol), potassium phosphate (0.24 mmol) andtricyclohexylphosphonium tetrafluoroborate (7 mg, 0.019 mmol) in toluene(1.5 mL) and water (70 μL) was added palladium acetate (2 mg, 0.003mmol). The mixture was stirred at 100° C. under nitrogen atmosphere for3 h and partitioned between water and ethyl acetate. The organic phasewas dried over Na₂SO₄ and concentrated in vacuo. Silica gelchromatography (DCM/EtOAc/MeOH) or reverse phase HPLC afforded thedesired pure 2-cyclic amino-thiazol-4-one product.

General Procedure G:

To a solution of an appropriate5-[1-(4-substituted-2-bromo)-1H-indazol-5-ylmethylene]-2-(cyclicamino)-thiazol-4-one (0.053 mmol), an appropriate substituted boronicacid (0.074 mmol), potassium phosphate (0.24 mmol) andtricyclohexylphosphonium tetrafluoroborate (7 mg, 0.019 mmol) in toluene(1.5 mL) and water (70 μL) was added palladium acetate (2 mg, 0.003mmol). The mixture was stirred at 100° C. under nitrogen atmosphere for3 h and partitioned between water and ethyl acetate. The organic phasewas dried over Na₂SO₄ and concentrated in vacuo. Silica gelchromatography (DCM/EtOAc/MeOH) or reverse phase HPLC afforded thedesired pure 2-cyclic amino-thiazol-4-one product.

General Procedure H:

Deprotection of t-Butyl Carbamate BOC tBuOC(O)N Using TrifluoroaceticAcid.

The BOC intermediate (1 mmol) was treated with TFA/DCM (0.3; 0.7 v/v).The mixture was stirred at room temperature for 2-4 hr and concentratedin vacuo. The residue was partitioned between EtOAc and a saturatedaqueous NaHCO₃ solution. The organic phase was dried and evaporated toafford the desired product. Silica gel chromatography (DCM/EtOAc/MeOH)or reverse phase HPLC afforded the desired pure 2-cyclicamino-thiazol-4-one product.

General Procedure I:

Deprotection of t-Butyl Carbamate BOC tBuOC(O)N using HCl

A solution of BOC intermediate (0.05 mmol) in MeOH (2 mL) and THF (1 mL)was treated with 4.0N HCl in 1,4-dioxane (2.5 mL) and stirred at roomtemperature for 12 hours. The solvent was removed in vacuo and theresidue recrystallized from methanol/diethyl ether to yield the desiredproduct Silica gel chromatography (DCM/EtOAc/MeOH) or reverse phase HPLCafforded the desired pure 2-cyclic amino-thiazol-4-one product.

Example 11-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carboxylicacid

A. 1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde wasprepared from 1H-Indazole-5-carbaldehyde and1-bromomethyl-2,4-bis-trifluoromethyl-benzene following GeneralProcedure A.

¹H NMR (400 MHz, CDCl₃): δ 10.08 9s, 1H), 8.34 (s, 1H), 8.31 (s, 1H),7.99 (s, 1H), 7.95 (dd, 1H), 7.63 (d, 1H), 7.37 (d, 1H), 6.82 (d, 1H),5.91 (s, 2H).

LC/MS: mass calcd. for C₁₇H₁₀F₆N₂O: 372.07, found 373.2 [M+H]⁺.

B.5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-thioxo-thiazolidin-4-onewas prepared from1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and2-thioxo-thiazolidin-4-one following General Procedure C.

LC/MS: mass calcd. for C₂₀H₁₁F₆N₄OS₂ (m/z), 487.0; found, 488.1 [M+H]⁺.

C.5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-onewas prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-thioxo-thiazolidin-4-oneand iodoethane following General Procedure C.

¹H NMR (400 MHz, CDCl₃): δ 8.24 (s, 1H), 7.98-8.01 (3H), 7.63 (d, 1H),7.55 (dd, 1H), 7.34 (d, 1H), 6.83 (d, 1H), 5.89 (s, 2H), 3.46 (q, 2H),1.50 (t, 3H).

LC/MS: mass calcd. for C₂₂H₁₅F₆N₃OS₂ (m/z), 515.1; found, 516.1 [M+H]⁺.

D.1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}piperidine-4-carboxylicacid was prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand piperidine-4-carboxylic acid following General Procedure C.

¹H NMR (400 MHz, CD₃OD): δ 8.25 (d, 1H), 8.08 (m, 1H), 8.05 (s, 1H),7.81 (s, 1H), 7.78 (d, 1H), 7.64 (dd, 1H), 7.56 (d, 1H), 6.85 (d, 1H),5.95 (s, 2H), 4.57 (m, 1H), 3.92 (m, 1H), 3.56 (m, 1H), 3.49 (m, 1H),2.75 (m, 1H), 2.12 (m, 2H), 1.82 (m, 2H).

LC/MS: mass calcd. for C₂₆H₂₀F₆N₄O₃S (m/z), 582.1; found, 583.3 [M+H]⁺.

Example 25-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one

5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-onewas prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand 1-methyl-piperazine following General Procedure C.

¹H NMR (400 MHz, CD₃OD): δ 8.28 (s, 1H), 8.15 (s, 1H), 8.06 (s, 1H),7.96 (s, 1H), 7.80 (d, 1H), 7.69 (dd, 1H), 7.60 (d, 1H), 6.88 (d, 1H),5.98 (s, 2H), 4.22 (br, 2H), 3.86 (br, 2H), 3.69 (br, 4H), 3.01 (s, 3H).

LC/MS: mass calcd. for C₂₅H₂₁F₆N₅OS (m/z), 553.1; found, 554.4 [M+H]⁺.

Example 35-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-morpholin-4-yl-thiazol-4-one

5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-morpholin-4-yl-thiazol-4-onewas prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand morpholine following General Procedure C.

¹H NMR (400 MHz, CDCl₃): δ 8.21 (s, 1H), 7.99 (s, 2H), 7.96 (s, 1H),7.63 (d, 1H), 7.56 (dd, 1H), 7.32 (d, 1H), 6.83 (d, 1H), 5.89 (s, 2H),4.11 (t, 2H), 3.86 (t, 2H), 3.83 (t, 2H), 3.66 (t, 2H).

LC/MS: mass calcd. for C₂₄H₁₆F₆N₄OS (m/z), 540.1; found, 541.4 [M+H]⁺.

Example 45-[1-(4-Fluoro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-thiazol-4-one

A. 1-(4-Fluoro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde wasprepared following General Procedure A.

¹H NMR (400 MHz, CDCl₃): δ 10.09 (s, 1H), 8.34 (s, 1H), 8.30 (s, 1H),7.96 (dd, 1H), 7.47 (dd, 1H), 7.40 (d, 1H), 6.77 (dd, 1H), 5.86 (s, 2H).

LC/MS: mass calcd. for C₁₆H₁₀F₄N₂O (m/z), 322.2; found, 323.3 [M+H]⁺.

B.5-[1-(4-Fluoro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-thiazol-4-onewas prepared from1-(4-Fluoro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and2-piperazin-1-yl-ethanol following General Procedure C.

¹H NMR (400 MHz, CDCl₃): δ 8.21 (s, 1H), 8.00 (s, 1H), 7.96 (s, 1H),7.57 (dd, 1H), 7.46 (dd, 1H), 7.35 (d, 1H), 7.09 (m, 1H), 6.77 (m, 1H),5.81 (s, 2H), 4.14 (t, 2H), 3.68-3.74 (4H), 2.65-2.75 (6H), 2.40 (t,1H).

LC/MS: mass calcd. for C₂₅H₂₃F₄N₅O₂S (m/z), 533.2; found, 534.4 [M+H]⁺.

Example 52-(4-Acetyl-piperazin-1-yl)-5-[1-(4-fluoro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one

2-(4-Acetyl-piperazin-1-yl)-5-[1-(4-fluoro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-onewas prepared from5-[1-(4-fluoro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand 1-piperazin-1-yl-ethanone following General Procedure C.

¹H NMR (400 MHz, CDCl₃): δ 8.12 (s, 1H), 7.91 (s, 1H), 7.47 (dd, 1H),7.37 (dd, 1H), 7.27 (d, 1H), 7.00 (m, 1H), 6.68 (m, 1H), 5.72 (s, 2H),4.05 9t, 1H), 4.01 (m, 1H), 3.76 (t, 1H), 3.72 (m, 1H), 3.54-3.62 (4H),2.11 (s, 3H).

LC/MS: mass calcd. for C₂₅H₂₁F₄N₅O₂S (m/z), 531.1; found, 532.4 [M+H]⁺.

Example 65-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-thiazol-4-one

5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-thiazol-4-onewas prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand 2-piperazin-1-yl-ethanol following General Procedure C.

¹H NMR (400 MHz, CDCl₃): δ 8.24 (s, 1H), 8.01 (s, 1H), 7.96 (s, 1H),7.65 (d, 1H), 7.58 (dd, 1H), 7.34 (d, 1H), 6.84 (d, 1H), 5.91 (s, 2H),4.15 (t, 2H), 3.72 (m, 4H), 2.75 (t, 2H), 2.69 (m, 4H).

LC/MS: mass calcd. for C₂₆H₂₃F₆N₅O₂S (m/z), 583.2; found, 584.4 [M+H]⁺

Example 75-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-piperazin-1-yl-thiazol-4-one

5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-piperazin-1-yl-thiazol-4-onewas prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand piperazine following General Procedure C.

¹H NMR (400 MHz, CD₃OD): δ 8.28 (d, 1H), 8.14 (d, 1H), 8.05 (s, 1H),7.88 (s, 1H), 7.79 (dd, 1H), 7.69 (dd, 1H), 7.59 (d, 1H), 6.87 (d, 1H),5.98 (s, 2H), 3.99 (t, 2H), 3.69 (t, 2H), 3.00 (t, 2H), 2.95 (t, 2H).

LC/MS: mass calcd. for C₂₄H₁₉F₆N₅O₂S (m/z), 539.1; found, 540.2 [M+H]⁺.

Example 85-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one

A. 1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde wasprepared from 1H-indazole-5-carbaldehyde and1-bromomethyl-4-chloro-2-trifluoromethyl-benzene following GeneralProcedure A.

LC/MS: mass calcd. for C16H10ClF3N2O (m/z), 338.71; found, 339.1 [M+H]⁺.

B.5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-onewas prepared from1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and1-methyl-piperazine following General Procedure C.

¹H NMR (400 MHz, CDCl₃): δ 8.18 (d, 1H), 7.97 (m, 1H), 7.93 (s, 1H),7.71 (d, 1H), 7.54 (dd, 1H), 7.29-7.35 (2H), 6.66 (d, 1H), 5.79 (s, 2H),4.09 (t, 2H), 3.66 (t, 2H), 2.58 (t, 2H), 2.54 (t, 2H), 2.37 (s, 3H).

LC/MS: mass calcd. for C₂₄H₂₁ClF₃N₅OS (m/z), 519.1; found, 520.3 [M+H]⁺.

Example 94-(5-{2-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-4-oxo-4H-thiazol-5-ylidenemethyl}-indazol-1-ylmethyl)-3-trifluoromethyl-benzonitrile

A. 4-Bromomethyl-3-trifluoromethyl-benzonitrile

A mixture of 4-methyl-3-trifluoromethyl-benzonitrile (370 mg, 2 mmol),N-Bromosuccinimide (356 mg, 2 mmol) and benzoyl peroxide (15 mg) in CCl₄(8 mL) was stirred at 85° C. for 16 hrs. The reaction mixture was thenpartitioned between saturated aqueous NaHCO₃ and DCM. DCM layer wasdried over Na₂SO₄, filtered, and the solvent evaporated in vacuo toyield a crude solid which was purified via flash chromatography (15%EtOAc in n-heptane) to yield the title compound as a solid (460 mg,85%).

¹H NMR (400 MHz, CDCl₃): δ 7.95 (s, 1H), 7.86 (dd, 1H), 7.77 (dd, 1H),4.63 (s, 2H).

B. 4-(5-Formyl-indazol-1-ylmethyl)-3-trifluoromethyl-benzonitrile wasprepared from 4-bromomethyl-3-trifluoromethyl-benzonitrile and1H-indazole-5-carbaldehyde following General Procedure A.

LC/MS: mass calcd. for C₁₇H₁₀F₃N₃O (m/z), 329.2; found, 330.2 [M+H]⁺.

C.4-(5-{2-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-4-oxo-4H-thiazol-5-ylidenemethyl}-indazol-1-ylmethyl)-3-trifluoromethyl-benzonitrilewas prepared from4-(5-Formyl-indazol-1-ylmethyl)-3-trifluoromethyl-benzonitrile and2-piperazin-1-yl-ethanol following General Procedure C.

¹H NMR (400 MHz, CDCl₃): δ 8.22 (d, 1H), 8.02 (br, 1H), 7.99 (m, 1H),7.94 (s, 1H), 7.65 (dd, 1H), 7.56 (dd, 1H), 7.31 (d, 1H), 6.80 (d, 1H),5.88 (s, 2H), 4.12 (t, 2H), 3.69 (m, 4H), 2.72 (t, 2H), 2.66 (m, 4H).

LC/MS: mass calcd. for C₂₆H₂₃F₃N₆O₂S (m/z), 540.2; found, 541.4 [M+H]⁺.

Example 104-{5-[2-(4-Methyl-piperazin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-indazol-1-ylmethyl}-3-trifluoromethyl-benzonitrile

4-{5-[2-(4-Methyl-piperazin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-indazol-1-ylmethyl}-3-trifluoromethyl-benzonitrilewas prepared from4-[5-(2-methylsulfanyl-4-oxo-4H-thiazol-5-ylidenemethyl)-indazol-1-ylmethyl]-3-trifluoromethyl-benzonitrileand 1-methyl-piperazine following General Procedure C.

¹H NMR (400 MHz, CDCl₃): δ 8.21 (d, 1H), 8.02 (br, 1H), 7.99 (m, 1H),7.93 (s, 1H), 7.65 (dd, 1H), 7.57 (dd, 1H), 7.30 (d, 1H), 6.80 (d, 1H),5.88 (s, 2H), 4.10 (t, 2H), 3.67 (t, 2H), 2.58 (t, 2H), 2.55 (t, 2H),2.37 (s, 3H).

LC/MS: mass calcd. for C₂₅H₂₁F₃N₆OS (m/z), 510.1; found, 511.4 [M+H]⁺.

Example 111-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-4-(R)-hydroxy-pyrrolidine-2-(S)-carboxylicacid

1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-4-(R)-hydroxy-pyrrolidine-2-(S)-carboxylicacid was prepared from5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand 4-(R)-hydroxy-pyrrolidine-2-(S)-carboxylic acid following GeneralProcedure C.

¹H NMR (400 MHz, CD₃OD): δ 8.24 (s, 1H), 8.05 (d, 1H), 7.82 (d, 1H),7.78 (m, 1H), 7.63 (dd, 1H), 7.55 (m, 1H), 7.47 (dd, 1H), 6.67 (d, 1H),5.84 (s, 2H), 4.60 (m, 1H), 3.91-4.05 (1H), 3.70 (m, 1H), 2.27-2.55(3H).

LC/MS: mass calcd. for C₂₄H₁₈ClF₃N₄O₄S (m/z), 550.1; found, 551.3[M+H]⁺.

Example 124-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazin-2-one

4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazin-2-onewas prepared from5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand piperazin-2-one following General Procedure C.

¹H NMR (400 MHz, CDCl₃): δ 8.21 (br, 1H), 7.98 (s, 2H), 7.72 (d, 1H),7.54 (d, 1H), 7.34 (d, 1H), 6.68 (d, 1H), 5.80 (s, 2H), 4.28-4.33 (3H),3.88 (m, 1H), 3.56-3.65 (m, 2H).

LC/MS: mass calcd. for C₂₃H₁₇ClF₃N₅O₂S (m/z), 519.1; found, 520.1[M+H]⁺.

Example 135-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-hydroxy-ethyl)piperazin-1-yl]-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-thiazol-4-onewas prepared from5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand 2-piperazin-1-yl-ethanol following General Procedure C.

¹H NMR (400 MHz, CD₃OD): δ 8.21 (d, 1H), 8.08 (br, 1H), 7.92 (s, 1H),7.79 (d, 1H), 7.63 (dd, 1H), 7.52 (d, 1H), 7.47 (dd, 1H), 6.69 (d, 1H),5.82 (s, 2H), 4.17 (br, 2H), 3.95 (t, 2H), 3.81 (br, 2H), 3.41 (t, 2H).

LC/MS: mass calcd. for C₂₅H₂₃ClF₃N₅O₂S (m/z), 549.1; found, 550.2[M+H]⁺.

Example 145-[1-(2,4-Dichloro-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]thiazol-4-one

A. 1-(2,4-Dichloro-benzyl)-1H-indazole-5-carbaldehyde was prepared from1H-indazole-5-carbaldehyde and 1-bromomethyl-2,4-dichloro-benzenefollowing General Procedure A.

LC/MS: mass calcd. for C₁₅H₁₀Cl₂N₂O (m/z), 305.1; found, 305.1 [M+H]⁺.

B.5-[1-(2,4-Dichloro-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-thiazol-4-onewas prepared from 1-(2,4-Dichloro-benzyl)-1H-indazole-5-carbaldehyde and2-piperazin-1-yl-ethanol following General Procedure C.

¹H NMR (400 MHz, CD₃OD): δ 8.16 (s, 1H), 8.03 (s, 1H), 7.91 (s, 1H),7.60 (s, 2H), 7.51 (s, 1H), 7.23 (dd, 1H), 6.85 (d, 1H), 4.86 (br, 1H),4.20 (br, 1H), 3.97 (t, 2H), 3.85 (br, 2H), 3.42 (t, 2H).

LC/MS: mass calcd. for C₂₄H₂₃Cl₂N₅O₂S (m/z), 515.1; found, 516.2 [M+H]⁺.

Example 155-[1-(4-Methanesulfonyl-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one

A. 4-Methylsulfanyl-2-trifluoromethyl-benzaldehyde

To a DMF solution (5 mL) containing 935.3 mg (4.87 mmol) of4-fluoro-2-(trifluoromethyl)benzaldehyde was added sodium thiomethoxide(414.2 mg, 5.84 mmol). The mixture was stirred at 90° C. for 2 h,partitioned between EtOAc and water. The EtOAc extracts were washed withbrine, dried over Na₂SO₄ and evaporated to afford desired product.

¹H NMR (400 MHz, CDCl₃): δ 10.30 (s, 1H), 8.05 (d, 1H), 7.54 (s, 1H),7.46 (d, 1H), 2.58 (s, 3H).

B. (4-Methylsulfanyl-2-trifluoromethyl-phenyl)-methanol

4-Methylsulfanyl-2-trifluoromethyl-benzaldehyde (4.87 mmol) wasdissolved in 5 mL of MeOH and the resulting solution was treated withNaBH₄ (221.1 mg, 5.84 mmol). The reaction mixture was stirred at roomtemperature for 2 h. The solvent was evaporated and the residue waspartitioned between CH₂Cl₂ and 1N HCl solution. The combined extractswere washed with brine, dried over Na₂SO₄. A small portion of extractswas evaporated to afford the desired product.

¹H NMR (400 MHz, CDCl₃): δ 7.59 (d, 1H), 7.48 (d, 1H), 7.40 (dd, 1H),4.80 (d, 2H), 2.51 (s, 3H).

C. (4-Methanesulfonyl-2-trifluoromethyl-phenyl)-methanol(4-Methylsulfanyl-2-trifluoromethyl-phenyl)-methanol (4.87 mmol) wasdissolved in 40 mL of CH₂Cl₂ and the resulting solution was treated withmCPBA (˜69.9% w/w mCPBA, 2.4 g). The reaction mixture was stirredovernight at room temperature. The excess mCPBA was quenched with aq.Na₂S₂O₃. The CH₂Cl₂ extracts were washed with 1N NaOH three times. Theorganic solvents were dried over Na₂SO₄ and evaporated to afford thedesired product.

¹H NMR (400 MHz, CDCl₃): δ 8.20 (s, 1H), 8.15 (dd, 1H), 8.07 (d, 1H),5.01 (d, 2H), 3.09 (s, 3H).

D. 1-Bromomethyl-4-methanesulfonyl-2-trifluoromethyl-benzene(4-Methanesulfonyl-2-trifluoromethyl-phenyl)-methanol (4.87 mmol) wasdissolved in 40 mL of CH₂Cl₂ and the resulting solution was treated withPBr₃ (1 N, 4.87 mL) at 0° C. for 4 h. The mixture was partitionedbetween CH₂Cl₂ and water. The combined CH₂Cl₂ extracts were washed withbrine, dried and evaporated. The residue was purified by flash columnchromatography on silica gel (heptane/EtOAc 3:1 v/v) to afford whitecrystals (1.24 g, 80%).

¹H NMR (400 MHz, CDCl₃): δ 8.23 (s, 1H), 8.13 (dd, 1H), 7.25 (d, 1H),4.66 (s, 2H), 3.11 (s, 3H).

E.1-(4-Methanesulfonyl-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehydewas prepared from 1H-indazole-5-carbaldehyde and1-bromomethyl-4-methanesulfonyl-2-trifluoromethyl-benzene followingGeneral Procedure A.

¹H NMR (400 MHz, CDCl₃): δ 10.08 (s, 1H), 8.31-8.36 (3H), 7.97 (dd, 1H),7.95 (dd, 1H), 7.38 (d, 1H), 6.91 (d, 1H), 5.94 (s, 2H), 3.06 (s, 3H).

F.5-[1-(4-Methanesulfonyl-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-onewas prepared from5-[1-(4-Methanesulfonyl-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-thioxo-thiazolidin-4-oneand methyl iodide following General Procedure C.

LC/MS: mass calcd. for C₂₁H₁₆F₃N₃O₃S₃ (m/z), 511.0; found, 512.1 [M+H]⁺.

G.5-[1-(4-Methanesulfonyl-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-onewas prepared from5-[1-(4-methanesulfonyl-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand 1-methyl-piperazine following General Procedure C.

¹H NMR (400 MHz, CDCl₃): δ 8.31 (d, 1H), 8.22 (d, 1H), 7.99 (m, 1H),7.91-7.95 (2H), 7.55 (d, 1H), 7.32 (d, 1H), 6.90 (d, 1H), 5.90 (s, 2H),4.11 (m, 2H), 3.67 (m, 2H), 3.07 (s, 3H), 2.56 (m, 4H), 2.38 (s, 3H).

LC/MS: mass calcd. for C₂₅H₂₄F₃N₅O₃S₂ (m/z), 563.1; found, 564.2 [M+H]⁺.

Example 162-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-5-[1-(4-methanesulfonyl-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one

2-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-5-[1-(4-methanesulfonyl-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-onewas prepared from5-[1-(4-methanesulfonyl-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand 2-piperazin-1-yl-ethanol following General Procedure C.

¹H NMR (400 MHz, CD₃OD): δ 8.31 (br, 1H), 8.26 (s, 1H), 8.08 (m, 1H),8.02 (d, 1H), 7.82 (s, 1H), 7.64 (d, 1H), 7.56 (d, 1H), 6.90 (d, 1H),5.97 (s, 2H), 4.02 (m, 2H), 3.73 (m, 2H), 3.31 (m, 4H), 3.15 (s, 3H),2.72 (t, 2H), 2.66 (t, 2H), 2.60 (t, 2H).

LC/MS: mass calcd. for C₂₆H₂₆F₃N₅O₄S₂ (m/z), 593.1; found, 594.2 [M+H]⁺.

Example 175-[1-(2-Chloro-4-methanesulfonyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one

5-[1-(2-Chloro-4-methanesulfonyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-onewas prepared from5-[1-(2-Chloro-4-methanesulfonyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand 1-methyl-piperazine following General Procedure C.

¹H NMR (400 MHz, CDCl₃): δ 8.19 (d, 1H), 8.02 (d, 1H), 7.98 (m, 1H),7.94 (s, 1H), 7.69 (dd, 1H), 7.58 (dd, 1H), 7.42 (d, 1H), 6.93 (d, 1H),5.78 (s, 2H), 4.10 (t, 2H), 3.67 (t, 2H), 3.04 (s, 3H), 2.58 (t, 2H),2.55 (t, 2H), 2.37 (s, 3H).

LC/MS: mass calcd. for C₂₄H₂₄ClN₅O₃S₂ (m/z), 529.1; found, 530.2 [M+H]⁺.

Example 184-{5-[1-(2-Chloro-4-methanesulfonyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazin-2-one

4-{5-[1-(2-Chloro-4-methanesulfonyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazin-2-onewas prepared from5-[1-(2-chloro-4-methanesulfonyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand piperazin-2-one following General Procedure C.

¹H NMR (400 MHz, CDCl₃): δ 8.22 (s, 1H), 8.02 (d, 1H), 7.99 (s, 2H),7.70 (dd, 1H), 7.58 (m, 1H), 7.45 (m, 1H), 6.94 (d, 1H), 5.79 (s, 2H),4.30 (s, 2H), 3.88 (t, 1H), 3.64 (t, 1H), 3.59 (m, 2H), 3.04 (s, 3H).

LC/MS: mass calcd. for C₂₃H₂₀ClN₅O₄S₂ (m/z), 529.1; found, 530.3 [M+H]⁺.

Example 195-[1-(2-Chloro-4-methanesulfonyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-thiazol-4-one

5-[1-(2-Chloro-4-methanesulfonyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-thiazol-4-onewas prepared from5-[1-(2-chloro-4-methanesulfonyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand 2-piperazin-1-yl-ethanol following General Procedure C.

¹H NMR (400 MHz, CDCl₃): δ 8.19 (d, 1H), 8.02 (d, 1H), 7.98 (m, 1H),7.94 (s, 1H), 7.69 (dd, 1H), 7.58 (dd, 1H), 7.42 (d, 1H), 6.93 (d, 1H),5.77 (s, 2H), 4.12 (t, 2H), 3.69 (m, 4H), 3.04 (s, 3H), 2.72 (t, 2H),2.66 (m, 4H).

LC/MS: mass calcd. for C₂₅H₂₆ClN₅O₄S₂ (m/z), 559.1; found, 560.3 [M+H]⁺.

Example 204-{5-[2-(4-Methyl-piperazin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-indazol-1-ylmethyl}-3-trifluoromethyl-benzamide

4-{5-[2-(4-Methyl-piperazin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-indazol-1-ylmethyl}-3-trifluoromethyl-benzonitrile(Example 10) (15.2 mg, 0.03 mmol) was dissolved in 1 mL of concentratedHCl and the mixture was stirred at 45° C. for 5 h. It was neutralizedwith aqueous 2N NaOH and extracted with EtOAc.

The EtOAc layer was dried over Na₂SO₄, filtered, and the solventevaporated in vacuo to yield the desired product (10.8 mg, 68% yield).

¹H NMR (400 MHz, CD₃OD): δ 8.31 (m, 1H), 8.27 (s, 1H), 8.13 (s, 1H),7.92 (dd, 1H), 7.87 (s, 1H), 7.67 (dd, 1H), 7.56 (d, 1H), 6.72 (d, 1H),5.95 (s, 2H), 4.03 (t, 2H), 3.74 (t, 2H), 3.34 (s, 3H), 2.63 (t, 2H),2.58 (t, 2H).

LC/MS: mass calcd. for C₂₅H₂₃F₃N₆O₂S (m/z), 528.2; found, 529.3 [M+H]⁺.

Example 215-[1-(4-Methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one

A. 1-Bromomethyl-4-methoxy-2-trifluoromethyl-benzene

A solution of (4-methoxy-2-trifluoromethyl-phenyl)-methanol (1.04 g, 5mmol) in DCM (20 mL) was treated at 0° C. with phosphorous tribromide(1.64 g, 6 mmol). The reaction mixture was stirred for 10 minutes at 0°C., 1 h at room temperature. The solvent was evaporated in vacuo toyield a crude oil which was purified via flash chromatography (10% DCMin hexane) to yield the title compound as an oil (1.36 g, 100%)

LC/MS: mass calcd. for C₆H₈BrF₃O (m/z), 269.06; found, 270 [M+H]⁺.

B. 1-(4-Methoxy-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde wasprepared from 1-bromomethyl-4-methoxy-2-trifluoromethyl-benzene and1H-indazole-5-carbaldehyde following General Procedure A.

LC/MS: mass calcd. for C₁₇H₁₃F₃N₂O₂ (m/z), 334.2; found, 335.2 [M+H]⁺.

C.5-[1-(4-Methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-onewas prepared from1-(4-Methoxy-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and1-methyl-piperazine following General Procedure C.

¹H NMR (400 MHz, CD₃OD): δ 8.22 (s, 1H), 8.12 (s, 1H), 7.94 (s, 1H),7.63 (m, 1H), 7.52 (d, 1H), 7.27 (d, 1H), 7.00 (m, 1H), 6.72 (d, 1H),5.79 (s, 2H), 3.81 (s, 3H), 3.20-3.70 (8H), 3.01 (s, 3H).

LC/MS: mass calcd. for C₂₅H₂₄F₃N₅O₂S (m/z), 515.2; found, 516.1 [M+H]⁺.

Example 225-[1-(4-Hydroxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one

To a solution of5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one(32 mg, 0.062 mmol) in CH₂Cl₂ (1 mL) was added 0.4 mL of 1M BBr₃ at −78°C. The mixture was stirred for 2 h at −78° C., then warmed up to roomtemperature. It was quenched with aqueous MeOH and NaHCO₃ solution,extracted with EtOAc. The combined organic extracts were evaporated andthe residue was purified by flash column chromatography on silica gel(0-100% gradient CH₂Cl₂/EtOAc, followed by 10% MeOH/EtOAc) to afford thetitle compound (30 mg, 96%).

¹H NMR (400 MHz, CD₃OD): δ 8.21 (s, 1H), 8.10 (s, 1H), 7.87 (s, 1H),7.64 (d, 1H), 7.50 (d, 1H), 7.14 (d, 1H), 6.82 (m, 1H), 6.61 (d, 1H),5.75 (s, 2H), 4.07 (m, 2H), 3.77 (m, 2H), 2.73 (m, 2H), 2.69 (m, 2H),2.44 (s, 3H).

LC/MS: mass calcd. for C₂₄H₂₂F₃N₅O₂S (m/z), 501.1; found, 502.2 [M+H]⁺.

Example 23 Methanesulfonic acid4-{5-[2-(4-methyl-piperazin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-indazol-1-ylmethyl}-3-trifluoromethyl-phenylester

To a solution of5-[1-(4-hydroxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one(10 mg, 0.02 mmol) in 1 mL CH₂Cl₂ was added DIEA (7.7 mg, 0.06 mmol) andmethanesulfonyl chloride (4 mg, 0.03 mmol). The mixture was stirred for1 h and loaded onto a silica gel-packed column. The desired product waseluted with 0-100% gradient of CH₂Cl₂/EtOAc, followed by 10% MeOH/EtOAc(8.6 mg, 74%).

¹H NMR (400 MHz, CDCl₃): δ 8.20 (s, 1H), 7.97 (s, 1H), 7.94 (s, 1H),7.64 (d, 1H), 7.56 (d, 1H), 7.34 (d, 1H), 7.30 (dd, 1H), 6.77 (d, 1H),5.83 (s, 2H), 4.13 (br, 2H), 3.70 (br, 2H), 3.19 (s, 3H), 2.62 (m, 4H),2.41 (s, 3H).

LC/MS: mass calcd. for C₂₅H₂₄F₃N₅O₄S₂ (m/z), 579.1; found, 580.2 [M+H]⁺.

Example 245-{1-[4-(2-Methoxy-ethoxy)-2-trifluoromethyl-benzyl]-1H-indazol-5-ylmethylene}-2-(4-methyl-piperazin-1-yl)-thiazol-4-one

5-[1-(4-Hydroxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one(24.7 mg, 0.049 mmol) was dissolved in 1 mL of dry DMF. To the DMFsolution was added Cs₂CO₃ (31.9 mg, 0.098 mmol), followed bymethoxyethyl bromide (9.6 mg, 0.07 mmol). The mixture was stirred at 60°C. for 16 h and then diluted with water. It was extracted with EtOAc andthe combined EtOAc extracts were washed with brine and dried overNa₂SO₄. The solvent was evaporated and the residue was purified by flashcolumn chromatography on silica gel (0-100% gradient CH₂Cl₂/EtOAc,followed by 10% MeOH/EtOAc) to afford the title compound (21 mg, 76%).

¹H NMR (400 MHz, CDCl₃): δ 8.16 (d, 1H), 7.96 (s, 1H), 7.93 (s, 1H),7.52 (dd, 1H), 7.31 (d, 1H), 7.28 (d, 1H), 6.89 (dd, 1H), 6.68 (d, 1H),5.75 (s, 2H), 4.10 (m, 4H), 3.73 (m, 2H), 3.66 (t, 2H), 3.43 (s, 3H),2.58 (t, 2H), 2.54 (t, 2H), 2.37 (s, 3H).

LC/MS: mass calcd. for C₂₇H₂₈F₃N₅O₃S (m/z), 559.2; found, 560.4 [M+H]⁺.

Example 255-[1-(2,4-Dichloro-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one

5-[1-(2,4-Dichloro-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-onewas prepared from5-[1-(2,4-dichloro-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 1-methyl-piperazine following General Procedure C.

¹H NMR (400 MHz, CDCl₃): δ 8.15 (s, 1H), 7.95 (d, 1H), 7.93 (s, 1H),7.55 (dd, 1H), 7.41-7.44 (2H), 7.13 (dd, 1H), 6.78 (d, 1H), 5.67 (s,2H), 4.10 (t, 2H), 3.66 (t, 2H), 2.58 (t, 2H), 2.55 (t, 2H), 2.37 (s,3H).

LC/MS: mass calcd. for C₂₃H₂₁Cl₂N₅OS (m/z), 485.1; found, 486.1 [M+H]⁺.

Example 265-[1-(4-Bromo-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one

A. 4-bromo-1-bromomethyl-2-trifluoromethyl-benzene was prepared from4-bromo-1-methyl-2-trifluoromethyl-benzene following the proceduredescribed for Example 9 (A).

¹H NMR (400 MHz, CDCl₃): 7.78 (d, 1H), 7.68 (dd, 1H), 7.47 (d, 1H), 4.57(s, 2H).

B. 1-(4-Bromo-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde wasprepared from 1H-indazole-5-carbaldehyde and4-bromo-1-bromomethyl-2-trifluoromethyl-benzene following GeneralProcedure A.

LC/MS: mass calcd. for C₁₆H₁₀BrF₃N₂O (m/z), 383.1; found, 385.0 [M+2H]⁺.

C.5-[1-(4-Bromo-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-onewas prepared from1-(4-Bromo-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and1-methyl-piperazine following General Procedure C.

¹H NMR (400 MHz, CDCl₃): δ 8.19 (s, 1H), 7.97 (s, 1H), 7.93 (s, 1H),7.86 (m, 1H), 7.55 (d, 1H), 7.49 (d, 1H), 7.31 (d, 1H), 6.59 (d, 1H),5.77 (s, 2H), 4.10 (t, 2H), 3.66 (t, 2H), 2.58 (t, 2H), 2.55 (t, 2H),2.37 (s, 3H).

LC/MS: mass calcd. for C₂₄H₂₁BrF₃N₅OS (m/z), 563.1; found, 564.2 [M+H]⁺.

Example 275-[1-(4-Cyclopropyl-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one

5-[1-(4-Cyclopropyl-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-onewas prepared from5-[1-(4-Bromo-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-oneand cyclopropyl boronic acid following General Procedure F.

¹H NMR (400 MHz, CD₃OD): δ 8.22 (s, 1H), 8.10 (s, 1H), 7.93 (s, 1H),7.63 (d, 1H), 7.49 (d, 1H), 7.46 (m, 1H), 7.11 (d, 1H), 6.57 (d, 1H),5.81 (s, 2H), 4.21 (br, 2H), 3.88 (br, 2H), 3.70 (br, 4H), 3.01 (s, 3H),1.96 (m, 1H), 1.01 (m, 2H), 0.69 (m, 2H).

LC/MS: mass calcd. for C₂₇H₂₆F₃N₅OS (m/z), 525.2; found, 526.3 [M+H]⁺.

Example 285-[1-(2-Bromo-4-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one

A. 2-Bromo-1-bromomethyl-4-trifluoromethyl-benzene was prepared from2-Bromo-1-methyl-4-trifluoromethyl-benzene following the proceduredescribed for Example 9 (A).

B. 1-(2-Bromo-4-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde wasprepared from 1H-indazole-5-carbaldehyde and2-bromo-1-bromomethyl-4-trifluoromethyl-benzene following GeneralProcedure A.

LC/MS: mass calcd. for C₁₆H₁₀BrF₃N₂O (m/z), 383.1; found, 385.0 [M+2H]⁺.

C.5-[1-(2-Bromo-4-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-onewas prepared from1-(2-Bromo-4-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde andN-methyl piperazine following General Procedure C.

¹H NMR (400 MHz, CD₃OD): δ 8.25 (s, 1H), 8.14 (s, 1H), 7.97 (s, 1H),7.96 (s, 1H), 7.69 (m, 2H), 7.56 (dd, 1H), 6.88 (d, 1H), 5.84 (s, 2H),4.22 (br, 2H), 3.84 (br, 2H), 3.69 (br, 4H), 3.01 (s, 3H).

LC/MS: mass calcd. for C₂₄H₂₁BrF₃N₅OS (m/z), 563.1; found, 564.2 [M+H]⁺.

Example 295-[1-(2-Cyclopropyl-4-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one

5-[1-(2-Cyclopropyl-4-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-onewas prepared from5-[1-(2-bromo-4-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-oneand cyclopropyl boronic acid following General Procedure G.

¹H NMR (400 MHz, CDCl₃): δ 8.19 (s, 1H), 7.96 (s, 1H), 7.93 (s, 1H),7.88 (s, 1H), 7.55 (m, 1H), 7.42 (m, 1H), 7.34 (m, 1H), 6.79 (d, 1H),5.73 (s, 2H), 4.13 (m, 2H), 3.70 (m, 2H), 2.61 (m, 4H), 1.99 (m, 1H),1.05 (m, 2H), 0.76 (m, 2H).

LC/MS: mass calcd. for C₂₇H₂₆F₃N₅OS (m/z), 525.2; found, 526.1 [M+H]⁺.

Example 305-[1-(4-Isopropenyl-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one

5-[1-(4-Isopropenyl-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-onewas prepared from5-[1-(4-bromo-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-oneand isopropenylboronic acid following General Procedure F.

¹H NMR (400 MHz, CDCl₃): δ 8.19 (d, 1H), 7.97 (m, 1H), 7.93 (s, 1H),7.79 (d, 1H), 7.53 (dd, 1H), 7.42 (dd, 1H), 7.33 (d, 1H), 6.66 (d, 1H),5.82 (s, 2H), 5.38 (s, 1H), 5.15 (m, 1H), 4.10 (t, 2H), 3.66 (t, 2H),2.58 (t, 2H), 2.55 (t, 2H), 2.37 (s, 3H), 2.12 (s, 3H).

LC/MS: mass calcd. for C₂₇H₂₆F₃N₅OS (m/z), 525.2; found, 526.2 [M+H]⁺.

Example 315-[1-(4-Cyclopropyl-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-thiazol-4-one

5-[1-(4-Cyclopropyl-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-hydroxy-ethyl)piperazin-1-yl]-thiazol-4-onewas prepared from5-[1-(4-bromo-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-thiazol-4-oneand cyclopropyl boronic acid following General Procedure F.

¹H NMR (400 MHz, CD₃OD): δ 8.22 (s, 1H), 8.10 (s, 1H), 7.94 (s, 1H),7.63 (dd, 1H), 7.50 (d, 1H), 7.47 (s, 1H), 7.11 (d, 1H), 6.57 (d, 1H),5.81 (s, 2H), 4.18 (br, 2H), 3.94 (t, 2H), 3.78 (br, 2H), 3.39 (t, 2H),1.96 (m, 1H), 1.01 (m, 2H), 0.69 (m, 2H).

LC/MS: mass calcd. for C₂₈H₂₈F₃N₆O₂S (m/z), 555.2; found, 556.2 [M+H]⁺.

Example 322-(3R,4R-Dihydroxy-pyrrolidin-1-yl)-5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one

2-(3R,4R-Dihydroxy-pyrrolidin-1-yl)-5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-onewas prepared from5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand pyrrolidine-3R,4R-diol following General Procedure C.

¹H NMR (400 MHz, DMSO-d₆): δ 8.29 (s, 1H), 8.10 (s, 1H), 7.76 (s, 1H),7.71 (d, 1H), 7.65 (dd, 1H), 7.25 (d, 1H), 7.11 (dd, 1H), 6.77 (d, 1H),5.76 (s, 2H), 5.55 (d, 1H), 5.49 (d, 1H), 4.11 (m, 2H), 3.83 (m, 2H),3.77 (s, 3H), 3.67 (m, 1H), 3.47 (m, 1H).

LC/MS: mass calcd. for C₂₄H₂₁F₃N₄O₄S (m/z), 518.1; found, 519.2 [M+H]⁺.

Example 33 1-{5-[1-(4-Methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carboxylicacid

1-{5-[1-(4-Methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carboxylicacid was prepared from5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand azetidine-3-carboxylic acid following General Procedure C.

¹H NMR (400 MHz, CD₃OD): δ 8.23 (d, 1H), 8.07 (s, 1H), 7.83 (s, 1H),7.61 (dd, 1H), 7.51 (d, 1H), 7.27 (d, 1H), 7.00 (dd, 1H), 6.68 (d, 1H),5.78 (s, 2H), 4.44-4.57 (4H), 3.81 (s, 3H), 3.55 (m, 1H).

LC/MS: mass calcd. for C₂₄H₁₉F₃N₄O₄S (m/z), 516.11; found, 517.3 [M+H]⁺.

Example 345-[1-(4-Methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-piperazin-1-yl-thiazol-4-one

5-[1-(4-Methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-piperazin-1-yl-thiazol-4-onewas prepared from5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand piperazine following General Procedure C.

¹H NMR (400 MHz, CDCl₃): δ 8.16 (d, 1H), 7.95 (s, 1H), 7.93 (s, 1H),7.52 (dd, 1H), 7.33 (d, 1H), 7.23 (d, 1H), 6.87 (dd, 1H), 6.70 (d, 1H),5.75 (s, 2H), 4.06 (t, 2H), 3.80 (s, 3H), 3.63 (t, 2H), 3.04 (t, 2H),3.00 (t, 2H).

LC/MS: mass calcd. for C₂₄H₂₂F₃N₅O₂S (m/z), 501.1; found, 502.3 [M+H]⁺.

Example 351-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carboxylicacid

1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carboxylicacid was prepared from5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand azetidine-3-carboxylic acid following General Procedure C.

¹H NMR (400 MHz, CD₃OD): δ 8.25 (s, 1H), 8.05 (s, 1H), 8.04 (s, 1H),7.81 (s, 1H), 7.78 (d, 1H), 7.61 (dd, 1H), 7.56 (d, 1H), 6.84 (d, 1H),5.95 (s, 2H), 4.54 (m, 2H), 4.49 (m, 2H), 3.69 (m, 1H).

LC/MS: mass calcd. for C₂₄H₁₆F₆N₄O₃S (m/z), 554.1; found, 555.3 [M+H]⁺.

Example 361-{5-[1-(4-Bromo-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carboxylicacid

1-{5-[1-(4-Bromo-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carboxylicacid was prepared from5-[1-(4-Bromo-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand azetidine-3-carboxylic acid following General Procedure C.

¹H NMR (400 MHz, CD₃OD): δ 8.26 (s, 1H), 8.09 (s, 1H), 7.93 (d, 1H),7.84 (s, 1H), 7.65 (dd, 1H), 7.63 (dd, 1H), 7.56 (d, 1H), 6.59 (d, 1H),5.84 (s, 2H), 4.43-4.58 (4H), 3.57 (m, 1H).

LC/MS: mass calcd. for C₂₃H₁₆BrF₃N₄O₃S (m/z), 564.0; found, 567.2[M+H+2]⁺.

Example 371-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-3-(S)-carboxylicacid

1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-3-(S)-carboxylicacid was prepared from5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand piperidine-3-(S)-carboxylic acid following General Procedure C.

¹H NMR (400 MHz, CD₃OD): δ 8.27 (d, 1H), 8.11 (d, 1H), 8.05 (s, 1H),7.83 (d, 1H), 7.79 (d, 1H), 7.66 (m, 1H), 7.58 (m, 1H), 6.84 (d, 1H),5.96 (s, 2H), 4.72 (m, 0.5H), 4.36 (m, 0.5H), 3.97 (m, 0.5H), 3.84 (m,0.5H), 3.47-3.75 (3H), 2.65 (m, 1H), 1.65-2.22 (4H).

LC/MS: mass calcd. for C₂₆H₂₀F₆N₄O₃S (m/z), 582.1; found, 583.3 [M+H]⁺.

Example 381-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-3-(R)-carboxylicacid

1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-3-(R)-carboxylicacid was prepared from5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand piperidine-3-(R)-carboxylic acid following General Procedure C.

¹H NMR (400 MHZ, CD₃OD): δ 8.26 (d, 1H), 8.09 (d, 1H), 8.05 (s, 1H),7.82 (s, 1H), 7.78 (d, 1H), 7.65 (m, 1H), 7.57 (m, 1H), 6.84 (d, 1H),5.96 (s, 2H), 4.59 (m, 1H), 3.90 (m, 1H), 3.63 (m, 1H), 3.53 (m, 1H),2.62 (m, 1H), 1.64-2.21 (4H).

LC/MS: mass calcd. for C₂₆H₂₀F₆N₄O₃S (m/z), 582.1; found, 583.3 [M+H]⁺

Example 391-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carboxylicacid

1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}piperidine-4-carboxylicacid was prepared from5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand piperidine-4-carboxylic acid following General Procedure C.

¹H NMR (CDCl₃): δ 8.19 (s, 1H), 7.97 (s, 1H), 7.94 (s, 1H), 7.71 (s,1H), 7.54 (d, 1H), 7.33 (d, 1H), 7.31 (d, 1H), 6.66 (d, 1H), 5.79 (s,2H), 4.66 (m, 1H), 3.89 (m, 1H), 3.56 (m, 1H), 3.47 (m, 1H), 2.78 (m,1H), 2.15 (m, 2H), 1.94 (m, 2H).

LC/MS: mass calcd. for C₂₅H₂₀ClF₃N₄O₃S (m/z), 548.1; found, 549.3[M+H]⁺.

Example 401-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carboxylicacid

1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carboxylicacid was prepared from5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand azetidine-3-carboxylic acid following General Procedure C.

¹H NMR (400 MHZ, CD₃OD): δ 8.25 (d, 1H), 8.09 (m, 1H), 7.85 (s, 1H),7.80 (d, 1H), 7.64 (dd, 1H), 7.56 (d, 1H), 7.48 (dd, 1H), 6.67 (d, 1H),5.86 (s, 2H), 4.58 (m, 2H), 4.51 (m, 2H), 3.77 (m, 1H).

LC/MS: mass calcd. for C₂₃H₁₆ClF₃N₄O₃S (m/z), 520.1; found, 521.3[M+H]⁺.

Example 411-{5-[1-(4-Methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carboxylicacid

1-{5-[1-(4-Methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carboxylicacid was prepared from5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand piperidine-4-carboxylic acid following General Procedure C.

¹H NMR (400 MHZ, DMSO-d₆): δ 8.27 (s, 1H), 8.09 (s, 1H), 7.73 (s, 1H),7.69 (d, 1H), 7.64 (d, 1H), 7.25 (d, 1H), 7.11 (dd, 1H), 7.64 (d, 1H),7.25 (d, 1H), 7.11 (dd, 1H), 6.77 (d, 1H), 5.75 (s, 2H), 4.37 (m, 1H),3.77 (s, 3H), 2.65-3.63H), 1.93 (m, 2H), 1.63 (m, 2H).

LC/MS: mass calcd. for C₂₆H₂₃F₃N₄O₄S (m/z), 544.1; found, 545.5 [M+H]⁺.

Example 425-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-[1,4]diazepan-1-yl)-thiazol-4-one

5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-[1,4]diazepan-1-yl)-thiazol-4-onewas prepared from5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand 1-methyl-[1,4]diazepane following General Procedure C.

¹H NMR (400 MHZ, CDCl₃): δ 8.21 (m, 1H), 7.98 (s, 2H), 7.92 (s, 1H),7.62 (d, 1H), 7.56 (dd, 1H), 7.31 (d, 1H), 6.81 (d, 1H), 5.88 (s, 2H),4.15 (m, 1H), 4.08 (t, 1H), 3.77 (t, 1H), 3.75 (t, 1H), 2.82 (m, 2H),2.70 (t, 1H), 2.66 (t, 1H), 2.43 (s, 3H), 2.17 (m, 2H), 2.05 (m, 2H).

LC/MS: mass calcd. for C₂₆H₂₃F₆N₆OS (m/z), 567.2; found, 568.4 [M+H]⁺.

Example 431-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-pyrrolidine-2-(R)-carboxylicacid

1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-pyrrolidine-2-(R)-carboxylicacid was prepared from5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand pyrrolidine-2-(R)-carboxylic acid following General Procedure C.

¹H NMR (400 MHZ, CDCl₃): δ 8.22 (d, 1H), 7.98 (m, 2H), 7.95 (s, 1H),7.63 (d, 1H), 7.53 (dd, 1H), 7.32 (d, 1H), 6.82 (d, 1H), 5.88 (s, 2H),4.97 (dd, 1H), 3.83 (m, 1H), 3.68 (m, 1H), 2.51 (m, 1H), 2.23-2.41 (2H),2.19 (m, 1H).

LC/MS: mass calcd. for C₂₅H₁₈F₆N₄O₃S (m/z), 568.1; found, 569.4 [M+H]⁺.

Example 441-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-pyrrolidine-2-(S)-carboxylicacid

1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-pyrrolidine-2-(S)-carboxylicacid was prepared from5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand pyrrolidine-2-(S)-carboxylic acid following General Procedure C.

¹H NMR (400 MHZ, CDCl₃): δ 8.19 (s, 1H), 7.94 (d, 1H), 7.92 (s, 1H),7.70 (d, 1H), 7.50 (dd, 1H), 7.33 (dd, 1H), 7.30 (d, 1H), 6.66 (d, 1H),5.77 (s, 2H), 4.97 (dd, 1H), 3.83 (m, 1H), 3.68 (m, 1H), 2.47 (m, 1H),2.37 (m, 1H), 2.27 (m, 1H), 2.18 (m, 1H).

LC/MS: mass calcd. for C₂₄H₁₈ClF₃N₄O₃S (m/z), 534.1; found, 535.4[M+H]⁺.

Example 45 1-{5-[1-(4-Methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-pyrrolidine-2-(R)-carboxylicacid

1-{5-[1-(4-Methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-pyrrolidine-2-(R)-carboxylicacid was prepared from5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand pyrrolidine-2-(R)-carboxylic acid following General Procedure C.

¹H NMR (400 MHZ, CDCl₃): δ 8.17 (d, 1H), 7.93 (s, 2H), 7.49 (dd, 1H),7.32 (d, 1H), 7.22 (d, 1H), 6.87 (dd, 1H), 6.70 (d, 1H), 5.74 (s, 2H),4.97 (dd, 1H), 3.83 (m, 1H), 3.79 (s, 3H), 3.68 (m, 1H), 2.48 (m, 1H),2.36 (m, 1H), 2.26 (m, 1H), 2.17 (m, 1H).

LC/MS: mass calcd. for C₂₅H₂₁F₃N₄O₄S (m/z), 530.1; found, 531.5 [M+H]⁺.

Example 461-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-pyrrolidine-2-(R)-carboxylicacid

1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-pyrrolidine-2-(R)-carboxylicacid was prepared from5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand pyrrolidine-2-(R)-carboxylic acid following General Procedure C.

¹H NMR (400 MHZ, CDCl₃): δ 8.19 (s, 1H), 7.95 (s, 1H), 7.93 (s, 1H),7.70 (d, 1H), 7.50 (dd, 1H), 7.33 (dd, 1H), 7.31 (d, 1H), 6.66 (d, 1H),5.78 (s, 2H), 5.75 (m, 1H), 4.99 (dd, 1H), 3.83 (m, 1H), 3.68 (m, 1H),2.47 (m, 1H), 2.38 (m, 1H), 2.26 (m, 1H), 2.18 (m, 1H).

LC/MS: mass calcd. for C₂₄H₁₈ClF₃N₄O₃S (m/z), 534.1; found, 535.4[M+H]⁺.

Example 471-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}piperazine-2-(R)-carboxylicacid

4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazine-1,3-dicarboxylicacid 1-tert-butyl ester was prepared from5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand piperazine-1,3-(R)-dicarboxylic acid 1-tert-butyl ester followingGeneral Procedure C. Compound was not isolated and1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazine-2-(R)-carboxylicacid acid was prepared following General Procedure H.

¹H NMR (400 MHZ, DMSO-d₆): δ 8.34 (s, 1H), 8.14 (d, 1H), 8.09 (s, 1H),7.95 (d, 1H), 7.79 (d, 1H), 7.77 (d, 1H), 7.68 (m, 1H), 6.89 (dd, 1H),5.96 (s, 2H), 5.06 (m, 1H), 2.50-4.20 (6H).

LC/MS: mass calcd. for C₂₅H₁₉F₆N₅O₃S (m/z), 583.1; found, 584.4 [M+H]⁺.

Example 481-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}piperidine-3-(S)-carboxylicacid

1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}piperidine-3-(S)-carboxylicacid was prepared from5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand piperidine-3-(R)-carboxylic acid following General Procedure C.

¹H NMR (400 MHZ, CDCl₃): δ 8.19 (d, 1H), 7.96 (d, 1H), 7.94 (d, 1H),7.71 (t, 1H), 7.53 (dd, 1H), 7.33 (m, 1H), 7.30 (d, 1H), 6.66 (dd, 1H),5.78 (s, 1H), 4.94 (dd, 1H), 4.53 (m, 0.5H), 3.95 (m, 0.5H), 3.80 (m,0.5H), 3.67 (m, 0.5H), 3.39-3.58 (m, 2H), 2.76 (m, 1H), 2.25 (m, 1H),1.67-2.06 (m, 2H).

LC/MS: mass calcd. for C₂₅H₂₀ClF₃N₄O₃S (m/z), 548.1; found, 549.4[M+H]⁺.

Example 491-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-2-(S)-carboxylicacid

1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-2-(S)-carboxylicacid was prepared from5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand azetidine-2-(S)-carboxylic acid following General Procedure C.

¹H NMR (400 MHZ, CDCl₃): δ 8.22 (s, 1H), 7.98 (s, 1H), 7.95 (br, 2H),7.63 (d, 1H), 7.50 (d, 1H), 7.32 (d, 1H), 6.82 (d, 1H), 6.07 (br, 1H),5.87 (s, 2H), 5.27 (m, 1H), 4.38 (m, 1H), 4.28 (m, 1H), 2.80-2.97 (2H).

LC/MS: mass calcd. for C₂₄H₁₆F₆N₄O₃S (m/z), 554.5; found, 555.4 [M+H]⁺.

Example 501-{5-[1-(4-Methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-2-(S)-carboxylicacid

1-{5-[1-(4-Methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-2-(S)-carboxylicacid was prepared from5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand azetidine-2-(S)-carboxylic acid following General Procedure C.

¹H NMR (400 MHZ, CD₃OD): δ 8.22 (d, 1H), 8.06 (d, 1H), 7.83 (s, 1H),7.59 (d, 1H), 7.51 (m, 1H), 7.27 (m, 1H), 7.00 (m, 1H), 6.68 (m, 1H),5.78 (s, 2H), 4.36 (m, 1H), 3.80 (s, 3H), 2.97 (m, 2H), 2.55 (m, 2H).

LC/MS: mass calcd. for C₂₄H₁₉F₃N₄O₄S (m/z), 516.1; found, 517.5 [M+H]⁺.

Example 512-(3-(S)-Amino-piperidin-1-yl)-5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one

(1-{5-[1-(4-Methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidin-3-yl)-carbamicacid tert-butyl ester was prepared from5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand piperidin-3-(S)-yl-carbamic acid tert-butyl ester following GeneralProcedure C. The compound was used directly following General ProcedureH to provide2-(3-(S)-Amino-piperidin-1-yl)-5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one.

¹H NMR (400 MHZ, CD₃OD): δ 8.20 (d, 1H), 8.07 (s, 1H), 7.89 (s, 1H),7.61 (dd, 1H), 7.48 (d, 1H), 7.27 (d, 1H), 7.00 (d, 1H), 6.70 (d, 1H),5.77 (s, 2H), 4.42 (m, 1H), 3.96 (m, 1H), 3.81 (s, 3H), 3.50-3.80 (3H),2.21 (m, 1H), 2.03 (m, 1H), 1.87 (m, 2H).

LC/MS: mass calcd. for C₂₅H₂₄F₃N₅O₂S (m/z), 515.2; found, 516.5 [M+H]⁺.

Example 522-(3-(S)-Amino-piperidin-1-yl)-5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one

(1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidin-3-yl)-carbamicacid tert-butyl ester was prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand piperidin-3-(S)-yl-carbamic acid tert-butyl ester following GeneralProcedure C. The compound was used directly following General ProcedureH to provide2-(3-(S)-Amino-piperidin-1-yl)-5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one.

¹H NMR (400 MHZ, CD₃OD): δ 8.27 (dd, 1H), 8.11 (s, 1H), 8.06 (s, 1H),7.85 (s, 1H), 7.79 (d, 1H), 7.67 (dt, 1H), 7.58 (d, 1H), 6.85 (dd, 1H),5.97 (s, 1H), 4.49 (m, 1H), 3.85 (m, 1H), 3.46 (m, 1H), 3.25 (m, 1H),2.94 (m, 1H), 1.88-2.10 (2H), 1.67 (m, 1H), 1.51 (m, 1H).

LC/MS: mass calcd. for C₂₅H₂₁F₆N₅OS (m/z), 553.1; found, 554.5 [M+H]⁺.

Example 532-(3-(R)-Amino-piperidin-1-yl)-5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one

(1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidin-3-yl)-carbamicacid tert-butyl ester was prepared prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand piperidin-3-(R)-yl-carbamic acid tert-butyl ester following GeneralProcedure C. The compound was used directly following General ProcedureH to provide2-(3-(R)-Amino-piperidin-1-yl)-5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one.

¹H NMR (400 MHZ, CDCl₃): δ 8.20 (dd, 1H), 7.98 (s, 1H), 7.97 (s, 1H),7.91 (s, 1H), 7.62 (d, 1H), 7.55 (m, 1H), 7.30 (dd, 1H), 6.81 (d, 1H),5.87 (s, 2H), 4.52 (m, 1H), 3.73 (m, 1H), 3.45 (m, 1H), 3.05-3.32 (2H),1.45-2.12 (4H).

LC/MS: mass calcd. for C₂₅H₂₁F₆N₅OS (m/z), 553.1; found, 554.5 [M+H]⁺.

Example 545-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[1,4]diazepan-1-yl-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[1,4]diazepan-1-yl-thiazol-4-onewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand [1,4]diazepane following General Procedure C.

¹H NMR (400 MHZ, CDCl₃): δ 8.19 (dd, 1H), 7.98 (d, 1H), 7.93 (d, 1H),7.71 (d, 1H), 7.55 (m, 1H), 7.33 (dd, 1H), 7.31 (m, 1H), 6.65 (d, 1H),5.79 (s, 2H), 4.09 (t, 1H), 4.06 (m, 1H), 3.79 (t, 1H), 3.71 (m, 1H),3.14 (m, 1H), 3.09 (m, 1H), 2.94 (m, 2H), 1.98 (m, 2H).

LC/MS: mass calcd. for C₂₄H₂₁Cl₃N₅OS (m/z), 519.1; found, 520.5 [M+H]⁺.

Example 555-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-[1,4]diazepan-1-yl-thiazol-4-one

5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[1,4]diazepan-1-yl-thiazol-4-onewas prepared from5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand [1,4]diazepane following General Procedure C.

¹H NMR (400 MHZ, CDCl₃): δ 8.22 (m, 1H), 7.99 (m, 1H), 7.98 (s, 1H),7.93 (s, 1H), 7.63 (d, 1H), 7.57 (d, 1H), 7.32 (d, 1H), 6.81 (d, 1H),5.89 (s, 2H), 4.08 (m, 2H), 3.79 (t, 1H), 3.72 (t, 1H), 3.14 (m, 1H),3.09 (m, 1H), 2.94 (m, 2H), 2.02 (m, 1H), 1.97 (m, 1H).

LC/MS: mass calcd. for C₂₅H₂₁F₆N₅OS (m/z), 553.1; found, 554.5 [M+H]⁺.

Example 565-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-methoxy-ethyl)-piperazin-1-yl]-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-methoxy-ethyl)-piperazin-1-yl]-thiazol-4-onewas prepared from5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 1-(2-methoxy-ethyl)-piperazine following General Procedure C.

¹H NMR (400 MHZ, CD₃OD): δ 8.21 (d, 1H), 8.07 (m, 1H), 7.92 (s, 1H),7.79 (d, 1H), 7.62 (dd, 1H), 7.52 (d, 1H), 7.47 (dd, 1H), 6.68 (d, 1H),5.82 (s, 1H), 3.97 (br, 2H), 3.81 (t, 2H), 3.80 (br, 2H), 3.50 (t, 2H),3.49 (br, 2H), 3.45 (s, 3H), 3.44 (br, 2H).

LC/MS: mass calcd. for C₂₆H₂₅ClF₃N₅O₂S (m/z), 563.1; found, 564.5[M+H]⁺.

Example 572-(4-Amino-piperidin-1-yl)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one

(1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidin-4-yl)-carbamicacid tert-butyl ester was prepared from5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand piperidin-4-yl-carbamic acid tert-butyl ester following GeneralProcedure C. The compound was used directly following General ProcedureH to provide2-(4-Amino-piperidin-1-yl)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one.

¹H NMR (400 MHZ, CDCl₃): δ 8.19 (d, 1H), 7.97 (m, 1H), 7.92 (s, 1H),7.71 (d, 1H), 7.54 (dd, 1H), 7.33 (dd, 1H), 7.31 (d, 1H), 6.65 (d, 1H),5.79 (s, 2H), 4.76 (m, 1H), 3.90 (m, 1H), 3.42 9m, 2H), 3.12 (m, 1H),2.02 (m, 2H), 1.28-1.68H).

LC/MS: mass calcd. for C₂₄H₂₁ClF₃N₅OS (m/z), 519.1; found, 520.4 [M+H]⁺.

Example 585-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2,2,2-trifluoro-ethyl)-piperazin-1-yl]-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2,2,2-trifluoro-ethyl)-piperazin-1-yl]-thiazol-4-onewas prepared from5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 1-(2,2,2-trifluoro-ethyl)piperazine following General Procedure C.

¹H NMR (400 MHZ, CD₃OD): δ 8.27 (s, 1H), 8.16 (s, 1H), 8.02 (s, 1H),7.80 (d, 1H), 7.67 (d, 1H), 7.59 (d, 1H), 7.49 (dd, 1H), 6.71 (d, 1H),5.87 (s, 2H), 4.06 (t, 2H), 3.87 (t, 2H), 3.38 (q, 2H), 3.06 (t, 2H),3.02 (t, 2H).

LC/MS: mass calcd. for C₂₅H₂₀ClF₆N₅OS (m/z), 587.1; found, 588.5 [M+H]⁺.

Example 592-(3-(R)-Amino-piperidin-1-yl)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one

(1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidin-3-yl)-carbamicacid tert-butyl ester was prepared from5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand piperidin-3-(R)-yl-carbamic acid tert-butyl ester following GeneralProcedure C. The compound was used directly following General ProcedureH to provide2-(3-(R)-Amino-piperidin-1-yl)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one.

¹H NMR (400 MHZ, CDCl₃): δ 8.19 (dd, 1H), 7.97 (s, 1H), 7.92 (s, 1H),7.71 (d, 1H), 7.54 (dd, 1H), 7.33 (dd, 1H), 7.31 (d, 1H), 6.66 (d, 1H),5.79 (s, 2H), 4.58 (m, 1H), 3.76 (m, 1H), 3.43 (m, 1H), 3.17 (m, 1H),3.06 (m, 1H), 1.47-2.12 (4H).

LC/MS: mass calcd. for C₂₄H₂₁ClF₃N₅OS (m/z), 519.1; found, 520.5 [M+H]⁺

Example 602-(3-(S)-Amino-piperidin-1-yl)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one

(1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidin-3-yl)-carbamicacid tert-butyl ester was prepared from5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand piperidin-3-(S)-yl-carbamic acid tert-butyl ester following GeneralProcedure C. The compound was used directly following General ProcedureH to provide2-(3-(S)-Amino-piperidin-1-yl)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one.

¹H NMR (400 MHZ, CDCl₃): δ 8.19 (s, 1H), 7.96 (s, 1H), 7.88 (s, 1H),7.71 (s, 1H), 7.53 (dd, 1H), 7.34 (m, 1H), 7.28 (m, 1H), 6.65 (m, 1H),5.78 (s, 2H), 4.57 (m, 1H), 3.76 (m, 1H), 3.43 (m, 1H), 3.20 (m, 1H),2.48 (br, 1H), 1.46-2.16 (4H).

LC/MS: mass calcd. for C₂₄H₂₁ClF₃N₅OS (m/z), 519.1; found, 520.5 [M+H]⁺.

Example 615-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2,2-difluoro-ethyl)-piperazin-1-yl]-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2,2-difluoro-ethyl)-piperazin-1-yl]-thiazol-4-onewas prepared from5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 1-(2,2-difluoro-ethyl)piperazine following General Procedure C.

¹H NMR (400 MHZ, CDCl₃): δ 8.18 (d, 1H), 7.96 (m, 1H), 7.93 (s, 1H),7.71 (d, 1H), 7.54 (dd, 1H), 7.33 (dd, 1H), 7.31 (d, 1H), 6.66 (d, 1H),5.99 (dt, 1H), 5.79 (s, 2H), 4.10 (t, 2H), 3.66 (t, 2H), 2.86 (m, 2H),2.80 (t, 2H), 2.76 (t, 2H).

LC/MS: mass calcd. for C₂₅H₂₁ClF₅N₅OS (m/z), 569.1; found, 570.5 [M+H]⁺.

Example 622-(3-(R)-Amino-pyrrolidin-1-yl)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one

(1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-pyrrolidin-3-yl)-carbamicacid tert-butyl ester was prepared from5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand pyrrolidin-3-(R)-yl-carbamic acid tert-butyl ester following GeneralProcedure C. The compound was used directly following General ProcedureH to provide2-(3-(R)-Amino-pyrrolidin-1-yl)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one.

¹H NMR (400 MHZ, CDCl₃): δ 8.17 (s, 1H), 7.94 (s, 1H), 7.89 (s, 1H),7.71 (d, 1H), 7.52 (m, 1H), 7.33 (dd, 1H), 7.29 (d, 1H), 6.64 (d, 1H),5.77 (s, 2H), 4.05 (m, 1/2H), 3.77-3.99 (3H), 3.67 (m, 1H), 3.35 (m,1/2H), 2.27 (m, 1H), 1.92 (m, 1H).

LC/MS: mass calcd. for C₂₃H₁₉ClF₃N₅OS (m/z), 505.1; found, 506.4 [M+H]⁺.

Example 635-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-ethyl-piperazin-1-yl)-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-ethyl-piperazin-1-yl)-thiazol-4-onewas prepared from5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 1-ethyl-piperazine following General Procedure C.

¹H NMR (400 MHZ, CDCl₃): δ 8.18 (d, 1H), 7.97 (m, 1H), 7.93 (s, 1H),7.71 (d, 1H), 7.54 (dd, 1H), 7.33 (dd, 1H), 7.31 (d, 1H), 6.66 (d, 1H),5.79 (s, 2H), 4.13 (br, 2H), 3.70 (t, 2H), 2.65 (m, 4H), 2.55 (q, 2H),1.15 (t, 3H).

LC/MS: mass calcd. for C₂₅H₂₃ClF₃N₅OS (m/z), 533.1; found, 534.5 [M+H]⁺.

Example 645-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(S)-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(S)-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-thiazol-4-onewas prepared from5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 2-((S)-1-methylpyrrolidino)-pyrrolidine following General ProcedureC.

¹H NMR (400 MHZ, CDCl₃): δ 8.20 (d, 1H), 7.96 (m, 1H), 7.92 (s, 1H),7.71 (d, 1H), 7.54 (m, 1H), 7.34 (m, 1H), 7.32 (m, 1H), 6.65 (m, 1H),5.79 (s, 2H), 4.59 (m, 1/2H), 4.08 (m, 1/2H), 3.60-3.92 (2H), 2.88-3.20(4H), 2.44-2.74 (2H), 2.05-2.31 (4H), 1.80-1.96 (4H).

LC/MS: mass calcd. for C₂₈H₂₇ClF₃N₅OS (m/z), 573.2; found, 574.3 [M+H]⁺.

Example 655-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2-(S),5-(S)-dimethyl-piperazin-1-yl)-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2,5-dimethyl-piperazin-1-yl)-thiazol-4-oneone was prepared from5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 2-(S),5-(S)-Dimethyl-piperazine following General Procedure C.

¹H NMR (400 MHZ, CDCl₃): δ 8.19 (s, 1H), 7.97 (s, 1H), 7.93 (s, 1H),7.71 (d, 1H), 7.55 (d, 1H), 7.33 (m, 1H), 7.32 (d, 1H), 6.66 (d, 1H),5.79 (s, 2H), 4.99-5.20 (1/2H), 4.48-4.68 (1/2H), 3.18-4.10 (4H),2.59-3.02 (1H), 0.99-1.99 (7H).

LC/MS: mass calcd. for C₂₅H₂₃ClF₃N₅OS (m/z), 533.1; found, 534.4 [M+H]⁺.

Example 665-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-methoxy-ethyl)-piperazin-1-yl]-thiazol-4-one

5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-methoxy-ethyl)-piperazin-1-yl]-thiazol-4-onewas prepared from5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand 1-(2-methoxy-ethyl)-piperazine following General Procedure C.

¹H NMR (400 MHZ, CDCl₃): δ 8.21 (s, 1H), 7.98 (s, 2H), 7.91 (s, 1H),7.62 (d, 1H), 7.55 (dd, 1H), 7.32 (d, 1H), 6.82 (d, 1H), 5.88 (s, 2H),4.12 (t, 2H), 3.69 (t, 2H), 3.55 (t, 2H), 3.38 (s, 3H), 2.70 (t, 2H),2.66 (m, 4H).

LC/MS: mass calcd. for C₂₇H₂₅F₆N₅O₂S (m/z), 597.2; found, 598.5 [M+H]⁺.

Example 675-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-ethyl-piperazin-1-yl)-thiazol-4-one

5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-ethyl-piperazin-1-yl)-thiazol-4-onewas prepared from5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand 1-ethyl-piperazine following General Procedure C.

¹H NMR (400 MHZ, CDCl₃): δ 8.21 (d, 1H), 7.98 (s, 2H), 7.92 (s, 1H),7.62 (d, 1H), 7.55 (dd, 1H), 7.32 (d, 1H), 6.82 (d, 1H), 5.89 (s, 2H),4.10 (t, 2H), 3.67 (t, 2H), 2.62 (t, 2H), 2.58 (t, 2H), 2.50 (q, 2H),1.13 (t, 3H).

LC/MS: mass calcd. for C₂₆H₂₃F₆N₅OS (m/z), 567.2; found, 568.4 [M+H]⁺.

Example 685-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-hydroxy-azetidin-1-yl)-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-hydroxy-azetidin-1-yl)-thiazol-4-onewas prepared from5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand azetidin-3-ol following General Procedure C.

¹H NMR (400 MHZ, DMSO-d₆): δ 8.34 (s, 1H), 8.10 (s, 1H), 7.88 (d, 1H),7.77 (s, 1H), 7.75 (s, 1H), 7.67 (m, 1H), 7.64 (m, 1H), 6.76 (d, 1H),6.13 (d, 1H), 5.85 (s, 2H), 4.72 (m, 1H), 4.53 (m, 2H), 4.08 (m, 2H).

LC/MS: mass calcd. for C₂₂H₁₆ClF₃N₄O₂S (m/z), 492.1; found, 493.4[M+H]⁺.

Example 695-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2S,5S-diaza-bicyclo[2.2.1]hept-2-yl)-thiazol-4-one

A.5-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester was prepared from5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand 2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl esterfollowing General Procedure C.

LC/MS: mass calcd. for C₃₀H₂₇F₆N₆O₃S (m/z), 651.2; found, 652.4 [M+H]⁺.

B.5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2S,5S-diaza-bicyclo[2.2.1]hept-2-yl)-thiazol-4-onewas prepared from5-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester following General Procedure H.

¹H NMR (400 MHZ, CDCl₃): δ 8.22 (s, 1H), 7.98 (s, 2H), 7.93 (s, 1H),7.62 (d, 1H), 7.55 (dd, 1H), 7.32 (d, 1H), 6.82 (d, 1H), 5.88 (s, 2H),5.21 (s, 1/2H), 4.46 (s, 1/2H), 3.98 (d, 1H), 3.81 (dd, 1H), 3.70 (d,1/2H), 3.47 (m, 1/2H), 3.17 (m, 2H), 1.98 (m, 2H).

LC/MS: mass calcd. for C₂₅H₁₉F₆N₅OS (m/z), 551.1; found, 552.4 [M+H]⁺.

Example 705-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(5-methyl-2S,5S-diaza-bicyclo[2.2.1]hept-2-yl)-thiazol-4-one

To a solution of5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2S,5S-diaza-bicyclo[2.2.1]hept-2-yl)-thiazol-4-one(50 mg, 0.091 mmol) in DCM (3 mL) was added 0.15 mL of 37% HCHOsolution, followed by 150 mg of NaBH(OAc)₃. The mixture was stirred for1 h and the solvents were removed under reduced pressure. The residuewas purified by flash column chromatography on silica gel (0-20%gradient EtOAc/MeOH) to afford the title compound (40 mg, 78%).

¹H NMR (400 MHZ, CD₃OD): δ 8.26 (d, 1H), 8.11 (d, 1H), 8.06 (s, 1H),7.97 (d, 1H), 7.79 (d, 1H), 7.65 (d, 1H), 7.58 (dd, 1H), 6.87 (m, 1H),5.95 (s, 2H), 5.28 (s, 1/2H), 5.01 (s, 1/2H), 4.64 (m, 1H), 4.02-4.20(3H), 3.40 (m, 1H), 3.08 (s, 3H), 2.63 (m, 1H), 2.48 (m, 1H).

LC/MS: mass calcd. for C₂₆H₂₁F₆N₅OS (m/z), 565.1; found, 566.2 [M+H]⁺.

Example 715-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[5-(2-hydroxy-ethyl)-2S,5S-diaza-bicyclo[2.2.1]hept-2-yl]-thiazol-4-one

5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[5-(2-hydroxy-ethyl)-2S,5S-diaza-bicyclo[2.2.1]hept-2-yl]-thiazol-4-onewas prepared from5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand 2-(2S,5S-diaza-bicyclo[2.2.1]hept-2-yl)ethanol following GeneralProcedure C.

¹H NMR (400 MHZ, CDCl₃): δ 8.21 (d, 1H), 7.98 (s, 1H), 7.97 (s, 1H),7.93 (s, 1H), 7.62 (d, 1H), 7.54 (m, 1H), 7.31 (d, 1H), 6.82 (d, 1H),5.88 (s, 2H), 5.15 (s, 1/2H), 4.40 (s, 1/2H), 3.49-4.07 (6H), 3.10 (m,1H), 2.75-2.90 (3H), 1.95-2.17H).

LC/MS: mass calcd. for C₂₇H₂₃F₆N₅O₂S (m/z), 595.2; found, 596.5 [M+H]⁺.

Example 722-(4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazin-1-yl)-N,N-dimethyl-acetamide

2-(4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazin-1-yl)-N,N-dimethyl-acetamideone was prepared from5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand N,N-dimethyl-2-piperazin-1-yl-acetamide following General ProcedureC.

¹H NMR (400 MHZ, CDCl₃): δ 8.19 (d, 1H), 7.97 (s, 1H), 7.93 (s, 1H),7.71 (d, 1H), 7.54 (dd, 1H), 7.33 (dd, 1H), 7.31 (d, 1H), 6.66 (d, 1H),5.79 (s, 2H), 4.14 (t, 2H), 3.69 (t, 2H), 3.28 (s, 2H), 3.06 (s, 3H),2.98 (s, 3H), 2.78 (t, 2H), 2.72 (t, 2H).

LC/MS: mass calcd. for C₂₇H₂₆ClF₃N₆O₂S (m/z), 590.2; found, 591.5[M+H]⁺.

Example 735-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-ethoxy-ethyl)-piperazin-1-yl]-thiazol-4-one

5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-ethoxy-ethyl)-piperazin-1-yl]-thiazol-4-onewas prepared from5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand 1-(2-ethoxy-ethyl)-piperazine following General Procedure C.

¹H NMR (400 MHZ, CDCl₃): δ 8.21 (s, 1H), 7.98 (s, 2H), 7.93 (s, 1H),7.63 (d, 1H), 7.55 (d, 1H), 7.31 (d, 1H), 6.81 (d, 1H), 5.88 (s, 2H),4.11 (t, 2H), 3.67 (t, 2H), 3.59 (t, 2H), 3.52 (q, 2H), 2.71 (t, 2H),2.66 (m, 4H), 1.22 (t, 3H).

LC/MS: mass calcd. for C₂₈H₂₇F₆N₅O₂S (m/z), 611.2; found, 612.5 [M+H]⁺.

Example 741-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-4-methyl-piperidine-4-carboxylicacid

1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-4-methyl-piperidine-4-carboxylicacid was prepared from5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand 4-methyl-piperidine-4-carboxylic acid following General Procedure C.

¹H NMR (400 MHZ, CDCl₃): δ 8.21 (s, 1H), 7.98 (s, 2H), 7.94 (s, 1H),7.62 (d, 1H), 7.55 (dd, 1H), 7.31 (d, 1H), 6.82 (d, 1H), 5.87 (s, 2H),4.69 (m, 1H), 3.74 (m, 1H), 3.56 (m, 1H), 3.45 (m, 1H), 2.32 (m, 2H),1.60 (m, 2H), 1.35 (s, 3H).

LC/MS: mass calcd. for C₂₇H₂₂F₆N₄O₃S (m/z), 596.1; found, 597.4 [M+H]⁺.

Example 751-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-4-methyl-piperidine-4-carboxylicacid

1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-4-methyl-piperidine-4-carboxylicacid was prepared from5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 4-methyl-piperidine-4-carboxylic acid following General Procedure C.

¹H NMR (400 MHZ, CDCl₃): δ 8.16 (s, 1H), 7.90 (s, 1H), 7.83 (s, 1H),7.69 (m, 1H), 7.48 (d, 1H), 7.32 (d, 1H), 7.27 (d, 1H), 6.65 (d, 1H),5.75 (s, 2H), 4.68 (br, 1H), 3.71 (m, 1H), 3.60 (m, 1H), 3.44 (m, 1H),2.35 (m, 1H), 2.28 (m, 1H), 1.40-1.54 (2H), 1.43 (s, 3H).

LC/MS: mass calcd. for C₂₆H₂₂ClF₃N₄O₃S (m/z), 562.1; found, 563.3[M+H]⁺.

Example 765-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-hydroxy-ethyl)-[1,4]diazepan-1-yl]-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-hydroxy-ethyl)-[1,4]diazepan-1-yl]thiazol-4-onewas prepared from5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 2-[1,4]diazepan-1-yl-ethanol following General Procedure C.

¹H NMR (400 MHZ, CD₃OD): δ 8.19 (s, 1H), 8.01 (m, 1H), 7.77 (dd, 1H),7.76 (d, 1H), 7.57 (dd, 1H), 7.48 (d, 1H), 7.45 (dd, 1H), 6.66 (d, 1H),5.79 (s, 2H), 3.96-4.03 (2H), 3.78 (m, 2H), 3.65 (m, 2H), 3.00 (m, 1H),2.92 (m, 1H), 2.78 (m, 2H), 2.69 (m, 2H), 2.05 (m, 1H), 1.96 (m, 1H).

LC/MS: mass calcd. for C₂₆H₂₅ClF₃N₅O₂S (m/z), 563.1; found, 564.3[M+H]⁺.

Example 772-(3-Amino-azetidin-1-yl)-5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one

(1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidin-3-yl)-carbamicacid tert-butyl ester was prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand azetidin-3-yl-carbamic acid tert-butyl ester following GeneralProcedure C. The compound was used directly following General ProcedureH to provide2-(3-Amino-azetidin-1-yl)-5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one.

¹H NMR (400 MHZ, CD₃OD): δ 8.27 (s, 1H), 8.10 (s, 1H), 8.05 (s, 1H),7.85 (s, 1H), 7.79 (d, 1H), 7.65 (dd, 1H), 7.58 (d, 1H), 6.85 (d, 1H),5.97 (s, 1H), 4.52-4.62 (2H), 4.04-4.12 (3H).

LC/MS: mass calcd. for C₂₃H₁₇F₆N₅OS (m/z), 525.5; found, 526.3 [M+H]⁺.

Example 785-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(5-methyl-2S,5S-diaza-bicyclo[2.2.1]hept-2-yl)-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(5-methyl-2S,5S-diaza-bicyclo[2.2.1]hept-2-yl)-thiazol-4-onewas prepared from5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 2-methyl-2S,5S-diaza-bicyclo[2.2.1]heptane following GeneralProcedure C.

¹H NMR (400 MHZ, CDCl₃): δ 8.17 (d, 1H), 7.94 (s, 1H), 7.91 (d, 1H),7.71 (d, 1H), 7.51 (m, 1H), 7.33 (dd, 1H), 7.29 (d, 1H), 6.66 (d, 1H),5.77 (s, 2H), 5.17 (s, 1/2H), 4.40 (s, 1/2H), 4.14 (d, 1/2H), 3.89 (d,1/2H), 2.79-3.86 (4H), 2.58 (d, 3H), 2.23 (m, 1H), 2.05 (m, 1H).

LC/MS: mass calcd. for C₂₅H₂₁ClF₃N₅OS (m/z), 531.1; found, 532.3 [M+H]⁺.

Example 792-(4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazin-1-yl)-acetamide

2-(4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazin-1-yl)-acetamidewas prepared from5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 2-piperazin-1-yl-acetamide following General Procedure C.

¹H NMR (400 MHZ, CD₃OD): δ 8.23 (s, 1H), 8.10 (s, 1H), 7.94 (s, 1H),7.80 (s, 1H), 7.65 (d, 1H), 7.54 (d, 1H), 7.48 (d, 1H), 6.69 (d, 1H),5.84 (s, 2H), 4.34 (br, 2H), 4.13 (s, 2H), 4.12 (br, 2H), 3.65 (br, 4H).

LC/MS: mass calcd. for C₂₅H₂₂ClF₃N₆O₂S (m/z), 562.1; found, 563.2[M+H]⁺.

Example 805-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[5-(2-hydroxy-ethyl)-2S,5S-diaza-bicyclo[2.2.1]hept-2-yl]-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[5-(2-hydroxy-ethyl)-2S,5S-diaza-bicyclo[2.2.1]hept-2-yl]-thiazol-4-onewas prepared from5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 2-(2S,5S-diaza-bicyclo[2.2.1]hept-2-yl)ethanol following GeneralProcedure C.

¹H NMR (400 MHZ, CD₃OD): δ 8.24 (s, 1H), 8.11 (s, 1H), 7.97 (d, 1H),7.80 (d, 1H), 7.65 (d, 1H), 7.57 (d, 1H), 7.49 (d, 1H), 6.70 (m, 1H),5.85 (s, 2H), 5.28 (s, 1/2H), 5.01 (m, 1/2H), 4.82-4.89 (1H), 3.40-4.31(4H), 2.42-2.64 (2H).

LC/MS: mass calcd. for C₂₆H₂₃ClF₃N₅O₂S (m/z), 561.1; found, 562.2[M+H]⁺.

Example 815-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-ethoxy-ethyl)-piperazin-1-yl]-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-ethoxy-ethyl)-piperazin-1-yl]-thiazol-4-onewas prepared from5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 1-(2-ethoxy-ethyl)-piperazine following General Procedure C.

¹H NMR (400 MHZ, CDCl₃): δ 8.18 (m, 1H), 7.97 (s, 1H), 7.92 (s, 1H),7.71 (d, 1H), 7.54 (dd, 1H), 7.33 (dd, 1H), 7.31 (d, 1H), 6.66 (d, 1H),5.79 (s, 2H), 4.10 (t, 2H), 3.67 (t, 2H), 3.59 (t, 2H), 3.52 9q, 2H),2.71 (t, 2H), 2.67 (m, 4H), 1.22 (t, 3H).

LC/MS: mass calcd. for C₂₇H₂₇ClF₃N₅O₂S (m/z), 577.2; found, 578.5[M+H]⁺.

Example 822-(4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}piperazin-1-yl)-N-methyl-acetamide

2-(4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazin-1-yl)-N-methyl-acetamidewas prepared from5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand N-methyl-2-piperazin-1-yl-acetamide following General Procedure C.

¹H NMR (400 MHZ, CD₃OD): δ 8.23 (d, 1H), 8.11 (m, 1H), 7.94 (s, 1H),7.80 (d, 1H), 7.65 (dd, 1H), 7.55 (d, 1H), 7.48 (dd, 1H), 6.70 (d, 1H),5.85 (s, 2H), 4.32 (br, 2H), 4.09 (br, 2H), 4.08 (s, 2H), 3.63 (m, 4H),2.83 (s, 3H).

LC/MS: mass calcd. for C₂₆H₂₄ClF₃N₆O₂S (m/z), 576.1; found, 577.2[M+H]⁺.

Example 835-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2-(R)-methyl-piperazin-1-yl)-thiazol-4-one

4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-3-methyl-piperazine-1-carboxylicacid tert-butyl ester was prepared from5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 3-(R)-methyl-piperazine-1-carboxylic acid tert-butyl ester followingGeneral Procedure C. The compound was used directly following GeneralProcedure H to provide5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2-(R)-methyl-piperazin-1-yl)thiazol-4-one.

¹H NMR (400 MHZ, CD₃OD): δ 8.25 (d, 1H), 8.13 (m, 1H), 7.95 (s, 1H),7.80 (d, 1H), 7.68 (dd, 1H), 7.57 (d, 1H), 7.49 (dd, 1H), 6.71 (d, 1H),5.86 (s, 2H), 5.23 (br, 1H), 4.52 (br, 1H), 3.45-4.09 (5H), 1.54 (m,3H).

LC/MS: mass calcd. for C₂₄H₂₁ClF₃N₅OS (m/z), 519.1; found, 520.2 [M+H]⁺.

Example 842-(4-tert-Butyl-piperazin-1-yl)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one

2-(4-tert-Butyl-piperazin-1-yl)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-onewas prepared from5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 1-tert-butyl-piperazine following General Procedure C.

¹H NMR (400 MHZ, CDCl₃): δ 8.19 (m, 1H), 7.97 (s, 1H), 7.93 (s, 1H),7.71 (d, 1H), 7.55 (dd, 1H), 7.33 (dd, 1H), 7.31 (d, 1H), 6.65 (d, 1H),5.79 (s, 2H), 4.07 (t, 2H), 3.63 (t, 2H), 2.74 (t, 2H), 2.70 (t, 2H),1.10 (s, 9H).

LC/MS: mass calcd. for C₂₇H₂₇ClF₃N₅OS (m/z), 561.2; found, 562.2 [M+H]⁺.

Example 855-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[5-(2-methoxy-ethyl)-2S,5S-diaza-bicyclo[2.2.1]hept-2-yl]-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[5-(2-methoxy-ethyl)-2S,5S-diaza-bicyclo[2.2.1]hept-2-yl]-thiazol-4-onewas prepared from5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 2-(2-methoxy-ethyl)-2S,5S-diaza-bicyclo[2.2.1]heptane followingGeneral Procedure C.

¹H NMR (400 MHZ, CDCl₃): δ 8.19 (s, 1H), 7.96 (s, 1H), 7.92 (s, 1H),7.71 (d, 1H), 7.53 (m, 1H), 7.33 (dd, 1H), 7.31 (d, 1H), 6.66 (d, 1H),5.79 (s, 2H), 5.09 (s, 1/2H), 4.35 (s, 1/2H), 4.10 (dd, 1/2H), 3.80 (m,1H), 3.66 (dd, 1/2H), 3.45-3.53 (3H), 3.36 (d, 3H), 3.24 (dd, 1/2H),3.08 (dd, 1/2H), 2.72-2.86 (3H), 2.14 (dd, 1H), 1.94 (dd, 1H).

LC/MS: mass calcd. for C₂₇H₂₅ClF₃N₅O₂S (m/z), 575.1; found, 576.2[M+H]⁺.

Example 865-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-methyl-3,8-diaza-bicyclo[3.2.1]oct-8-yl)-thiazol-4-one

5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-methyl-3,8-diaza-bicyclo[3.2.1]oct-8-yl)-thiazol-4-onewas prepared from5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand 3-methyl-3,8-diaza-bicyclo[3.2.1]octane following General ProcedureC.

¹H NMR (400 MHZ, CDCl₃): δ 8.21 (d, 1H), 7.98 (s, 2H), 7.93 (s, 1H),7.62 (d, 1H), 7.55 (dd, 1H), 7.32 (d, 1H), 6.82 (d, 1H), 5.89 (s, 2H),4.96 (m, 1H), 4.16 (m, 1H), 2.84 (dd, 1H), 2.76 (dd, 1H), 2.46 (dd, 1H),2.40 (dd, 1H), 2.29 (s, 3H), 2.02-2.20 (4H).

LC/MS: mass calcd. for C₂₇H₂₃F₆N₅OS (m/z), 579.2; found, 580.1 [M+H]⁺.

Example 875-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-methyl-3,8-diaza-bicyclo[3.2.1]oct-8-yl)-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-methyl-3,8-diaza-bicyclo[3.2.1]oct-8-yl)-thiazol-4-onewas prepared from5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 3-methyl-3,8-diaza-bicyclo[3.2.1]octane following General ProcedureC.

¹H NMR (400 MHZ, CDCl₃): δ 8.19 (s, 1H), 7.96 (s, 1H), 7.92 (s, 1H),7.71 (d, 1H), 7.54 (dd, 1H), 7.33 (dd, 1H), 7.31 (dd, 1H), 6.66 (d, 1H),5.79 (s, 2H), 4.96 (m, 1H), 4.17 (m, 1H), 2.81 (dd, 2H), 2.43 (dd, 2H),2.29 (s, 3H), 2.01-2.17H).

LC/MS: mass calcd. for C₂₆H₂₃ClF₃N₅OS (m/z), 545.1; found, 546.1 [M+H]⁺.

Example 885-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-methoxy-acetyl)cis-3,5-dimethyl-piperazin-1-yl]-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-methoxy-acetyl)-cis-3,5-dimethyl-piperazin-1-yl]-thiazol-4-oneone was prepared from5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 1-(2,6-dimethyl-piperazin-1-yl)-2-methoxy-ethanone following GeneralProcedure C.

¹H NMR (400 MHZ, CDCl₃): δ 8.21 (s, 1H), 7.97 (s, 2H), 7.71 (d, 1H),7.54 (d, 1H), 7.33 (m, 2H), 6.68 (d, 1H), 5.79 (s, 2H), 4.87 (m, 2H),4.08-4.24 (3H), 3.60-3.75 (2H), 3.47 (s, 3H), 3.37 (m, 1H).

LC/MS: mass calcd. for C₂₈H₂₇ClF₃N₅O₃S (m/z), 605.2; found, 606.1[M+H]⁺.

Example 895-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[5-(2-methoxy-acetyl)-2S,5S-diaza-bicyclo[2.2.1]hept-2-yl]-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[5-(2-methoxy-acetyl)-2S,5S-diaza-bicyclo[2.2.1]hept-2-yl]-thiazol-4-onewas prepared from5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 1-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-2-methoxy-ethanone followingGeneral Procedure C.

¹H NMR (400 MHZ, CDCl₃): δ 8.17 (m, 1H), 7.94 (m, 1H), 7.90 (m, 1H),7.70 (m, 1H), 7.50 (m, 1H), 7.33 (m, 1H), 7.30 (m, 1H), 6.66 (m, 1H),5.77 (s, 2H), 5.34 (s, 1/2H), 5.17 (s, 1/2H), 4.98 (d, 1/2H), 4.62 (d,1/2H), 3.40-4.22 (9H), 2.13 (m, 2H).

LC/MS: mass calcd. for C₂₇H₂₃ClF₃N₅O₃S (m/z), 589.1; found, 590.1[M+H]⁺.

Example 905-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-methoxy-acetyl)-2-(R)-methyl-piperazin-1-yl]-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-methoxy-acetyl)-2-(R)-methyl-piperazin-1-yl]-thiazol-4-onewas prepared from5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 2-Methoxy-1-(3-(R)-methyl-piperazin-1-yl)-ethanone following GeneralProcedure C.

¹H NMR (400 MHZ, CDCl₃): δ 8.20 (s, 1H), 7.98 (s, 1H), 7.96 (s, 1H),7.71 (d, 1H), 7.54 (d, 1H), 7.34 (dd, 1H), 7.32 (m, 1H), 6.68 (d, 1H),5.79 (s, 2H), 5.21 (m, 1H), 4.47-4.87 (2H), 3.87-4.29 (4H), 3.24-3.54(7H), 2.86-3.11 (1H).

LC/MS: mass calcd. for C₂₇H₂₅ClF₃N₅O₃S (m/z), 591.1; found, 592.1[M+H]⁺.

Example 915-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-methoxy-acetyl)-piperazin-1-yl]-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-methoxy-acetyl)-piperazin-1-yl]-thiazol-4-onewas prepared from5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 2-methoxy-1-piperazin-1-yl-ethanone following General Procedure C.

¹H NMR (400 MHZ, CDCl₃): δ 8.19 (s, 1H), 7.97 (s, 1H), 7.95 (s, 1H),7.71 (d, 1H), 7.53 (d, 1H), 7.34 (dd, 1H), 7.31 (d, 1H), 6.67 (d, 1H),5.78 (s, 2H), 4.17 (s, 2H), 4.11 (br, 2H), 3.49-3.86 (6H), 3.45 (s, 3H).

LC/MS: mass calcd. for C₂₆H₂₃ClF₃N₅O₃S (m/z), 577.1; found, 578.1[M+H]⁺.

Example 922-(3-Amino-azetidin-1-yl)-5-[1-(4-chloro-2-cyclopropyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one

A. 2-Bromo-1-bromomethyl-4-chloro-benzene was prepared from2-bromo-4-chloro-1-methyl-benzene following the procedure described forExample 9 (A).

B. 1-(2-Bromo-4-chloro-benzyl)-1H-indazole-5-carbaldehyde was preparedfrom 1H-indazole-5-carbaldehyde and2-bromo-1-bromomethyl-4-chloro-benzene following General Procedure A.

¹H NMR (400 MHZ, CDCl₃): 10.03 (s, 1H), 8.27 (s, 1H), 8.24 (s, 1H), 7.91(s, 1H), 7.59 (m, 1H), 7.45 (d, 1H), 7.14 (d, 1H), 6.69 (d, 1H), 5.78(s, 2H).

LC/MS: mass calcd. for C₁₆H₁₀BrClN₂O, 349.61; m/z found, 349.0 [M+H]⁺.

C. 1-(4-Chloro-2-cyclopropyl-benzyl)-1H-indazole-5-carbaldehyde

To a N₂ flushed vial was added1-(2-bromo-4-chloro-benzyl)-1H-indazole-5-carbaldehyde (250 mg, 0.71mmol), Pd₂(dba)₃ (47 mg, 0.05 mmol), biphenyl-2-yl-di-t-butyl-phosphane(42 mg, 0.14 mmol), Cs₂CO₃ (296 mg, 0.9 mmol) cyclopropaneboronic acid(86 mg, 1 mmol) and dioxane (3 mL). The resulting mixture was heated at90° C. for 16 h. The resulting mixture was poured into water andextracted with EtOAc. The organic layer was dried and concentrated, andthe residue was purified by preparative HPLC to yield4-chloro-r-thiophen-3-yl-pyridine as a white solid.

¹H NMR (400 MHZ, CDCl₃): 10.04 (s, 1H), 8.28 (s, 1H), 8.22 (s, 1H), 7.89(d, 1H), 7.38 (d, 1H), 7.07 (m, 2H), 6.72 (d, 1H), 5.78 (s, 2H), 1.91(m, 1H), 0.95 (m, 2H), 0.69 (m, 2H).

LC/MS: mass calcd. for C₁₈H₁₁ClN₂O, 310.1; m/z found, 311.1 [M+H]⁺.

D.(1-{5-[1-(4-Chloro-2-cyclopropyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidin-3-yl)-carbamicacid tert-butyl ester was prepared from1-(4-Chloro-2-cyclopropyl-benzyl)-1H-indazole-5-carbaldehyde andazetidin-3-yl-carbamic acid tert-butyl ester following General ProcedureC.

LC/MS: mass calcd. for C₂₉H₃₀ClN₅O₃S, 564.1; m/z found, 564.3 [M+H]⁺.

E.2-(3-Amino-azetidin-1-yl)-5-[1-(4-chloro-2-cyclopropyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-onewas prepared from(1-{5-[1-(4-Chloro-2-cyclopropyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidin-3-yl)-carbamicacid tert-butyl ester following General Procedure H.

¹H NMR (400 MHZ, CDCl₃): 8.08 (s, 1H), 7.86 (s, 2H), 7.42 (d, 1H), 7.26(d, 1H), 7.04 (m, 2H), 6.70 (d, 1H), 5.71 (s, 2H), 4.65 (t, 1H), 4.47(t, 1H), 4.20-396 (m, 3H), 1.89 (m, 1H), 0.96 (m, 2H), 0.67 (m, 2H).

LC/MS: mass calcd. for C₂₄H₂₂ClN₅OS, 463.1; m/z found, 462.1 [M+H]⁺.

Example 935-[1-(4-Chloro-2-cyclopropyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one

5-[1-(4-Chloro-2-cyclopropyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-onewas prepared from5-[1-(4-chloro-2-cyclopropyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand 1-methyl-piperazine following General Procedure C.

¹H NMR (400 MHZ, CDCl₃): 8.14 (s, 1H), 7.96 (s, 1H), 7.93 (s, 1H), 7.51(d, 1H), 7.32 (d, 1H), 7.07 (m, 2H), 6.73 (d, 1H), 5.76 (s, 2H), 4.11(t, 2H), 3.65 (t, 2H), 2.56 (m, 4H), 2.37 (s, 3H), 1.91 (m, 1H), 0.97(m, 2H), 0.70 (m, 2H).

LC/MS: mass calcd. for C₂₆H₂₆ClN₅OS, 491.2; m/z found, 492.3[M+H]⁺.

Example 941-(5-[1-(4-Chloro-2-cyclopropyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-dihydro-thiazol-2-yl)-azetidine-3-carboxylicacid

1-(5-[1-(4-Chloro-2-cyclopropyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-dihydro-thiazol-2-yl]-azetidine-3-carboxylicacid was prepared from5-[1-(4-chloro-2-cyclopropyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand azetidine-3-carboxylic acid following General Procedure C.

¹H NMR (400 MHZ, DMSO): 8.29 (s, 1H), 8.09 (s, 1H), 7.78 (s, 1H), 7.77(d, 1H), 7.63 (d, 1H), 7.15 (dd, 1H), 7.07 (m, 1H), 6.74 (d, 1H), 5.85(s, 2H), 4.52 (t, 2H), 4.38 (m, 2H), 3.71 (m, 1H), 2.12 (m, 1H), 0.90(m, 2H), 0.70 (m, 2H).

LC/MS: mass calcd. for C₂₅H₂₁ClN₄O₃S, 492.1; m/z found, 493.4[M+H]⁺.

Example 955-[1-(2-bromo-4-chlorobenzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one

5-[1-(2-bromo-4-chlorobenzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-onewas prepared from5-[1-(2-bromo-4-chloro-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand 1-methyl-piperazine following General Procedure C.

¹H NMR (400 MHZ, CDCl₃): 8.16 (s, 1H), 7.96 (d, 1H), 7.93 (s, 1H), 7.62(d, 1H), 7.55 (dd, 1H), 7.41 (d, 1H), 7.16 (dd, 1H), 6.70 (d, 1H), 5.65(s, 2H), 4.10 (t, 2H), 3.67 (t, 2H), 2.56 (m, 4H), 2.37 (s, 3H).

LC/MS: mass calcd. for C₂₃H₂₁BrClN₅OS, 529.0; m/z found, 530.4 [M+H]⁺.

Example 965-[1-(4-Chloro-2-iodo-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one

A. 1-Bromomethyl-4-chloro-2-iodo-benzene was prepared from4-chloro-2-iodo-1-methyl-benzene following the procedure described forExample 9 (A).

¹H NMR (400 MHZ, CDCl₃): 7.85 (d, 1H), 7.39 (d, 1H), 7.32 (dd, 1H), 4.56(s, 2H).

B. 1-(4-Chloro-2-iodo-benzyl)-1H-indazole-5-carbaldehyde was preparedfrom 1H-indazole-5-carbaldehyde and1-Bromomethyl-4-chloro-2-iodo-benzene following General Procedure A.

C.5-[1-(4-Chloro-2-iodo-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-onewas prepared from 1-(4-Chloro-2-iodo-benzyl)-1H-indazole-5-carbaldehydeand 1-methyl-piperazine following General Procedure C.

¹H NMR (400 MHZ, CDCl₃): 8.17 (s, 1H), 7.96 (d, 1H), 7.94 (s, 1H), 7.89(d, 1H), 7.55 (dd, 1H), 7.39 (d, 1H), 7.19 (dd, 1H), 6.59 (d, 1H), 5.60(s, 2H), 4.10 (t, 2H), 3.67 (t, 2H), 2.57 (m, 4H), 2.37 (s, 3H).

LC/MS: mass calcd. for C₂₃H₂₁IClN₅OS, 577.0; m/z found, 578.2 [M+H]⁺.

Example 975-[1-(2-Acetyl-4-chloro-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one

5-[1-(2-Acetyl-4-chloro-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-onewas prepared following General Procedure G.

To a N₂ flushed vial was added5-[1-(4-chloro-2-iodo-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)thiazol-4-one(100 mg, 0.15 mmol), Pd₂(dba)₃ (10 mg, 0.011 mmol),biphenyl-2-yl-di-t-butyl-phosphane (12 mg, 0.04 mmol),Tributyl-(1-ethoxy-vinyl)-stannane (86 mg, 0.23 mmol) and dioxane (2mL). The resulting mixture was heated at 90° C. for 16 h. The resultingmixture was poured into water and extracted with EtOAc. The organiclayer was dried and concentrated, and the residue was purified bypreparative HPLC to yield a white solid which was treated 1 Nhydrochloric acid in MeOH to yield the title compound.

¹H NMR (400 MHZ, CDCl₃): 8.14 (s, 1H), 7.95 (s, 1H), 7.93 (s, 1H), 7.81(d, 1H), 7.53 (dd, 1H), 7.39 (d, 1H), 7.30 (dd, 1H), 6.56 (d, 1H), 5.91(s, 2H), 4.09 (t, 2H), 3.66 (t, 2H), 2.62 (s, 3H), 2.55 (m, 4H), 2.36(s, 3H).

LC/MS: mass calcd. for C₂₅H₂₄ClN₅O₂S, 493.1; m/z found, 494.3[M+H]⁺.

Example 982-(3-Amino-azetidin-1-yl)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one

A.(1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidin-3-yl)-carbamicacid tert-butyl ester was prepared from5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand azetidin-3-yl-carbamic acid tert-butyl ester following GeneralProcedure C.

LC/MS: mass calcd. for C₂₇H₂₅ClF₃N₅O₃S, 592.03; m/z found, 592.5 [M+H]⁺.

B.2-(3-Amino-azetidin-1-yl)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-onewas prepared from(1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidin-3-yl)-carbamicacid tert-butyl ester following General Procedure H.

¹H NMR (400 MHZ, CDCl₃): 8.14 (s, 1H), 7.91 (s, 1H), 7.89 (s, 1H), 7.70(d, 1H), 7.49 (dd, 1H), 7.32 (dd, 1H), 7.27 (d, 1H), 6.64 (d, 1H), 5.76(s, 2H), 4.67 (t, 1H), 4.49 (t, 1H), 4.21-3.97 (m, 3H).

LC/MS: mass calcd. for C₂₂H₁₇ClF₃N₅OS, 491.1; m/z found, 492.5 [M+H]⁺.

Example 995-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3R,4R-dihydroxy-pyrrolidin-1-yl)-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3,4-dihydroxy-pyrrolidin-1-yl)-thiazol-4-onewas prepared from5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand pyrrolidine-3R,4R-diol following General Procedure C.

¹H NMR (400 MHZ, DMSO): 8.23 (s, 1H), 8.11 (s, 1H), 7.87 (d, 1H), 7.77(s, 1H), 7.67 (d, 1H), 7.67 (dd, 1H), 7.63 (dd, 1H), 6.74 (d, 1H), 5.85(s, 2H), 5.53 (d, 1H), 5.46 (d, 1H), 4.11 (d, 2H), 3.83 (td, 2H), 3.67(d, 1H), 3.47 (d, 1H).

LC/MS: mass calcd. for C₂₃H₁₈ClF₃N₄O₃S, 522.1; m/z found, 523.2 [M+H]⁺.

Example 1005-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2S,5S-diaza-bicyclo[2.2.1]hept-2-yl)-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-thiazol-4-onewas prepared from5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 2S,5S-diaza-bicyclo[2.2.1]heptane following General Procedure C.

¹H NMR (400 MHZ, CDCl₃): 8.18 (s, 0.45H), 8.16 (s, 0.55H), 7.94 (m, 1H),7.90 (s, 1H), 7.70 (d, 1H), 7.51 (m, 1H), 7.34-7.27 (m, 2H), 7.27 (d,1H), 6.64 (d, 0.45H), 6.63 (d, 0.55H), 5.78 (s, 0.9H), 5.77 (s, 1.1H),5.20 (s, 0.55H), 4.45 (s, 0.45H), 3.97-3.12 (m, 5H), 2.02 (m, 2H).

LC/MS: mass calcd. for C₂₄H₁₉ClF₃N₅OS, 517.1; m/z found, 518.4 [M+H]⁺.

Example 1015-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(8-methyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(8-methyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-thiazol-4-onewas prepared from5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 8-methyl-3,8-diaza-bicyclo[3.2.1]octane following General ProcedureC.

¹H NMR (400 MHZ, CDCl₃): 8.18 (s, 1H), 7.96 (s, 1H), 7.92 (s, 1H), 7.70(d, 1H), 7.54 (dd, 1H), 7.30 (m, 2H), 6.66 (d, 1H), 5.79 (s, 2H), 4.96(s, 1H), 3.16 (s, 1H), 2.79 (dd, 2H), 2.43 (dd, 2H), 2.28 (s, 3H),2.25-2.05 (m, 4H).

LC/MS: mass calcd. for C₂₆H₂₃ClF₃N₅OS, 545.1; m/z found, 546.4 [M+H]⁺.

Example 1025-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-oxo-azetidin-1-yl)-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-oxo-azetidin-1-yl)-thiazol-4-onewas prepared from5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand azetidin-3-one following General Procedure C.

¹H NMR (400 MHZ, CDCl₃): 8.19 (s, 1H), 7.99 (s, 1H), 7.96 (s, 1H), 7.71(d, 1H), 7.52 (dd, 1H), 7.33 (m, 2H), 6.68 (d, 1H), 5.79 (s, 2H), 5.22(s, 2H), 5.09 (s, 2H).

LC/MS: mass calcd. for C₂₂H₁₄ClF₃N₄O₂S, 490.1; m/z found, 491.1 [M+H]⁺.

Example 1035-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(8-methyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-thiazol-4-one

5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(8-methyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-thiazol-4-onewas prepared from5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand 8-methyl-3,8-diaza-bicyclo[3.2.1]octane following General ProcedureC.

¹H NMR (400 MHZ, CDCl₃): 8.21 (s, 1H), 7.98 (s, 2H), 7.93 (s, 1H), 7.62(d, 1H), 7.55 (d, 1H), 7.31 (d, 1H), 6.82 (d, 1H), 5.88 (s, 2H), 4.97(s, 1H), 4.16 (s, 1H), 2.79 (dd, 2H), 2.43 (dd, 2H), 2.29 (s, 3H),2.24-2.06 (m, 4H).

LC/MS: mass calcd. for C₂₇H₂₃F₆N₅OS, 579.2; m/z found, 530.4[M+H]⁺.

Example 1045-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2-hydroxymethyl-piperazin-1-yl)-thiazol-4-one

A.4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-3-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester was prepared from5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand 3-(R)-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl esterfollowing General Procedure C.

LC/MS: mass calcd. for C₃₀H₂₉F₆N₅O₄S, 669.6; m/z found, 670.2 [M+H]⁺.

B.5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2-hydroxymethyl-piperazin-1-yl)-thiazol-4-onewas prepared from4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-3-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester following General Procedure H.

¹H NMR (400 MHZ, CDCl₃): 8.20 (m, 1H), 7.98-7.89 (m, 3H), 7.63-7.51 (m,2H), 7.30 (m, 1H), 6.80 (m, 1H), 5.86 (m, 2H), 4.89-4.79 (m, 1H),4.23-2.88 (m, 10H).

LC/MS: mass calcd. for C₂₅H₂₁F₆N₅O₂S, 569.1; m/z found, 570.2 [M+H]⁺.

Example 1055-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2-hydroxymethyl-piperazin-1-yl)-thiazol-4-one

A.4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-3-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester was prepared from5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 3-(R)-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl esterfollowing General Procedure C.

LC/MS: mass calcd. for C₂₉H₂₉ClF₃N₅O₄S, 636.09; m/z found, 636.3 [M+H]⁺.

B.5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2-hydroxymethyl-piperazin-1-yl)-thiazol-4-onewas prepared from4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-3-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester following General Procedure H.

¹H NMR (400 MHZ, CDCl₃): 8.14 (m, 1H), 7.92-7.85 (m, 2H), 7.70 (m, 1H),7.51-7.47 (m, 1H), 7.33-7.22 (m, 2H), 6.64 (m, 1H), 5.73 (m, 2H),4.85-4.74 (m, 1H), 4.22-2.86 (m, 10H).

LC/MS: mass calcd. for C₂₄H₂₁ClF₃N₅O₂S, 535.1; m/z found, 536.1 [M+H]⁺.

Example 1061-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carboxylicacid amide

1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carboxylicacid amide was prepared from541-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand piperidine-4-carboxylic acid amide following General Procedure B.

¹H NMR (400 MHz, DMSO) δ 8.35 (s, 1H), 8.16-8.11 (m, 2H), 7.97 (d, 1H),7.81-7.77 (m, 2H), 7.72-7.70 (dd, 1H), 7.38 (br s, 1H), 6.92-6.90 (m,2H), 5.98 (s, 2H), 4.58-4.55 (m, 1H), 3.90-3.85 (m, 1H), 3.54-3.47 (m,1H), 3.38-3.30 (m, 2H), 1.96-1.86 (m, 2H), 1.66-1.56 (m, 2H).

LC/MS (m/z) [M+1]⁺ 582.2 (calculated for C₂₆H₂₁F₆N₅O₂S, 581.53).

Example 1075-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-isocyano-piperidin-1-yl)-thiazol-4-one

5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-isocyano-piperidin-1-yl)-thiazol-4-onewas prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand 4-Isocyano-piperidine following General Procedure B.

¹H NMR (400 MHz, DMSO) δ 8.35 (s, 1H), 8.16-8.12 (m, 2H), 7.97 (d, 1H),7.82-7.79 (m, 2H), 7.72-7.70 (dd, 1H), 6.91 (d, 1H), 5.98 (s, 2H),4.22-4.16 (m, 1H), 3.82-3.72 (m, 2H), 3.66-3.61 (m, 1H), 3.30-3.25 (m,1H), 2.13-1.02 (m, 2H), 1.96-1.84 (m, 2H).

LC/MS (m/z) [M+1]⁺ 564.3 (calculated for C₂₆H₁₉F₆N₅OS, 563.52).

Example 108N—(1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidin-4-yl)-acetamide

N—(1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidin-4-ylacetamidewas prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand N-Piperidin-4-yl-acetamide following General Procedure B.

¹H NMR (400 MHz, CD₃CN) δ 8.24 (s, 1H), 8.10-8.08 (m, 2H), 7.80 (s, 1H),7.76-7.74 (m, 1H), 7.67-7.64 (dd, 1H), 7.56-7.64 (m, 1H), 6.85 (d, 1H),6.70-6.68 (m, 1H), 5.92 (s, 2H), 4.63-4.58 (m, 1H), 4.01-3.96 (m, 1H),3.86-3.81 (m, 1H), 3.54-3.38 (m, 2H), 2.08-1.96 (m, 2H), 1.95 (s, 3H),1.59-1.50 (m, 2H).

LC/MS (m/z) [M+1]⁺ 596.2 (calculated for C₂₇H₂₃F₆N₅O₂S, 595.56).

Example 1095-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(1H-tetrazol-5-yl)piperidin-1-yl]-thiazol-4-one

A. 4-(1H-Tetrazol-5-yl)-piperidine-1-carboxylic acid benzyl ester

A mixture of 4-cyano-piperidine-1-carboxylic acid benzyl ester (0.73 g,3.0 mmol), sodium azide (0.39 g, 6.0 mmol) and zinc bromide (0.33 g, 1.5mmol) in 2-propanol (5 mL) and water (10 mL) was stirred at 120° C. for3 days into a pressure tube. The reaction mixture was then partitionedbetween aqueous 3.0N HCl (1.5 mL) and ethyl acetate and then stirredvigorously until 2 clear phases were obtained. Aqueous layer was thenextracted with ethyl acetate and combined ethyl acetate layers driedover Na₂SO₄, filtered, and the solvent evaporated in vacuo to yield acrude residue. The residue was dissolved in ethyl acetate (10 mL) andwashed with 0.25N aqueous sodium hydroxide. Aqueous layer was acidifiedto pH=1 with aqueous 3.0N HCl and extracted with ethyl acetate. Ethylacetate layer was dried over Na₂SO₄, filtered, and the solventevaporated in vacuo to yield a crude gum. The gum was purified via flashchromatography (4% methanol in dichloromethane) to yield4-(1H-Tetrazol-5-yl)-piperidine-1-carboxylic acid benzyl ester as a gum(1.14 g, 66%).

¹H NMR (400 MHz, CDCl₃) δ 7.36-7.29 (m, 5H), 5.16 (br s, 2H), 4.27-4.24(m, 2H), 3.34-3.27 (m, 1H), 3.06-2.98 (m, 2H), 2.16-2.06 (m, 2H),1.82-1.77 (m, 2H)

LC/MS (m/z) [M+1]⁺ 288.3 (calculated for C₁₄H₁₇N₅O₂, 287.32).

B. 4-(1H-Tetrazol-5-yl)-piperidine

A mixture of 4-(1H-Tetrazol-5-yl)-piperidine-1-carboxylic acid benzylester (0.6 g, 2.08 mmol) and activated 10 wt. % palladium on carbon(0.065 g) in ethanol (35 mL) was stirred vigorously under 1 atmospherehydrogen atmosphere for 4 hours. The reaction mixture was then filteredthrough a microglass filter paper and the solid washed abundantly withmethanol and water. The solvent was evaporated in vacuo to yield the4-(1H-tetrazol-5-yl)-piperidine as a white solid (0.30 g, 94%).

¹H NMR (400 MHz, CDCl₃) δ 3.32-3.27 (m, 2H), 3.15-3.08 (m, 2H),3.04-2.97 (m, 2H), 2.01-2.05 (m, 2H), 1.87-1.77 (m, 2H).

LC/MS (m/z) [M+1]⁺ 154.2 (calculated for C₆H₁₁N₅, 153.19).

C.5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(1H-tetrazol-5-A-piperidin-1-yl]-thiazol-4-one

5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(1H-tetrazol-5-yl)-piperidin-1-yl]-thiazol-4-onewas prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand 4-(1H-tetrazol-5-yl)-piperidine following General Procedure B.

¹H NMR (400 MHz, DMSO) δ 8.28 (s, 1H), 8.14 (s, 1H), 8.07 (s, 1H), 7.89(s, 1H), 7.79-7.77 (m, 1H), 7.69 (dd, 1H), 7.60-7.58 (m, 1H), 6.87-6.84(m, 1H), 5.96 (s, 2H), 4.80-4.74 (m, 1H), 4.05-4.02 (m, 1H), 3.72-3.65(m, 1H), 3.59-3.47 (m, 2H), 2.35-2.23 (m, 2H), 2.03-1.92 (m, 2H).

LC/MS (m/z) [M+1]⁺ 607.1 (calculated for C₂₆H₂₀F₆N₈OS, 606.55).

Example 1105-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(1H-tetrazol-5-yl)-piperidin-1-yl]-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(1H-tetrazol-5-yl)-piperidin-1-yl]-thiazol-4-onewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand 4-(1H-tetrazol-5-yl)-piperidine following General Procedure B.

¹H NMR (00 MHz, DMSO) δ 8.32 (s, 1H), 8.15 (s, 1H), 7.89-7.88 (m, 1H),7.81 (s, 1H), 7.79-7.76 (m, 1H), 7.70 (dd, 1H), 7.67-7.65 (m, 1H),6.78-6.76 (m, 1H), 5.87 (s, 2H), 4.62-4.58 (m, 1H), 3.97-3.93 (m, 1H),3.72-3.67 (m, 1H), 3.59-3.47 (m, 2H), 2.26-2.17 (m, 2H), 1.90-1.82 (m,2H).

LC/MS (m/z) [M+1]⁺ 573.0 (calculated for C₂₅H₂₀ClF₃N₈OS, 572.99).

Example 111N—(1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidin-4-yl)-methanesulfonamide

N—(1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidin-4-yl)-methanesulfonamidewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand N-piperidin-4-yl-methanesulfonamide following General Procedure B.

¹H NMR (400 MHz, CDCl₃) δ 8.18 (s, 1H), 7.96-7.94 (m, 2H), 7.71 (d, 1H),7.53 (dd, 1H), 7.34-7.28 (m, 2H), 6.67-6.65 (m, 1H), 5.78 (s, 2H),4.83-4.79 (m, 1H), 4.70 (d, 1H), 3.90-3.86 (m, 1H), 3.72-3.68 (m, 1H),3.52-3.36 (m, 2H), 3.05 (s, 3H), 2.29-2.14 (m, 2H), 1.75-1.66 (m, 2H).

LC/MS (m/z) [M+1]⁺ 598.2 (calculated for C₂₅H₂₃ClF₃N₅O₃S₂, 598.06).

Example 1125-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methoxy-piperidin-1-yl)-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methoxy-piperidin-1-yl)-thiazol-4-onewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand 4-methoxy-piperidine following General Procedure B.

¹H NMR (400 MHz, CDCl₃) δ 8.18 (s, 1H), 7.97 (s, 1H), 7.92 (s, 1H), 7.71(d, 1H), 7.54 (dd, 1H), 7.34-7.29 (m, 2H), 6.66-6.64 (m, 1H), 5.79 (s,2H), 4.19-4.00 (m, 2H), 3.83-3.77 (m, 1H), 3.63-3.58 (m, 1H), 3.56-3.49(m, 1H), 3.40 (s, 3H), 1.98-1.82 (m, 4H).

LC/MS (m/z) [M+1]⁺ 535.2 (calculated for C₂₅H₂₂ClF₃N₄O₂S, 534.98).

Example 1135-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-methoxy-azetidin-1-yl)-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-methoxy-azetidin-1-yl)-thiazol-4-onewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand 3-methoxy-azetidine following General Procedure B.

¹H NMR (400 MHz, CDCl₃) δ 8.18 (s, 1H), 7.94-7.92 (m, 2H), 7.71 (d, 1H),7.52 (dd, 1H), 7.34-7.29 (m, 2H), 6.66-6.64 (m, 1H), 5.79 (s, 2H),4.61-4.57 (m, 1H), 4.48-4.41 (m, 2H), 4.32-4.29 (m, 1H), 4.20-4.17 (m,1H), 3.38 (s, 3H).

LC/MS (m/z) [M+1]⁺ 507.1 (calculated for C₂₃H₁₈ClF₃N₄O₂S, 506.93).

Example 1141-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-[1,4]diazepan-5-one

1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-[1,4]diazepan-5-onewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand [1,4]diazepan-5-one following General Procedure B.

¹H NMR (400 MHz, CDCl₃) δ 8.20 (dd, 1H), 7.98 (br s, 2H), 7.71 (d, 1H),7.56-7.53 (m, 1H), 7.35-7.31 (m, 2H), 6.69-6.67 (m, 1H), 6.12 (br s,1H), 5.79 (s, 2H), 4.27-4.24 (m, 2H), 3.84-3.82 (m, 2H), 3.53-3.45 (m,2H), 2.84-2.78 (m, 2H).

LC/MS (m/z) [M+1]⁺ 534.1 (calculated for C₂₄H₁₉ClF₃N₅O₂S, 533.95).

Example 1155-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-methylamino-pyrrolidin-1-yl)-thiazol-4-one

A.(1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-pyrrolidin-3-yl)-methyl-carbamicacid tert-butyl ester was prepared from5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand methyl-pyrrolidin-3-yl-carbamic acid tert-butyl ester followingGeneral Procedure B.

¹H NMR (400 MHz, CDCl₃) δ 8.19 (dd, 1H), 7.97-7.94 (m, 2H), 7.71 (d,1H), 7.56-7.52 (m, 1H), 7.34-7.30 (m, 2H), 6.66-6.64 (m, 1H), 5.79 (s,2H), 4.18-4.05 (m, 1H), 3.85-3.74 (m, 2H), 3.69-3.49 (m, 2H), 2.84 (d,3H), 2.34-2.17 (m, 2H), 1.49 (d, 9H).

LC/MS (m/z) [M+1]⁺ 620.0 (calculated for C₂₉H₂₉ClF₃N₅O₃S, 620.09).

B.5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-methylamino-pyrrolidin-1-yl)-thiazol-4-onewas prepared from(1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-pyrrolidin-3-yl)-methyl-carbamicacid tert-butyl ester following General Procedure I.

¹H NMR (400 MHz, DMSO) δ 8.35 (s, 1H), 8.14 (s, 1H), 7.89 (d, 1H),7.83-7.78 (m, 2H), 7.71-7.65 (m, 2H), 6.78-6.76 (m, 1H), 5.87 (s, 2H),4.06-3.75 (m, 5H), 2.64-2.62 (m, 3H), 2.45-2.32 (m, 2H).

LC/MS (m/z) [M+1]⁺ 520.1 (calculated for C₂₄H₂₁ClF₃N₅OS, 519.97).

Example 116N—(1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-pyrrolidin-3-yl)-2,2,2-trifluoro-acetamide

N—(1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-pyrrolidin-3-yl)-2,2,2-trifluoro-acetamidewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand 2,2,2-Trifluoro-N-pyrrolidin-3-yl-acetamide following GeneralProcedure B.

¹H NMR (400 MHz, DMSO) δ 8.35 (dd, 1H), 8.14 (br s, 2H), 7.89 (s, 1H),7.80-7.76 (m, 2H), 7.71-7.65 (m, 2H), 6.77-6.75 (m, 1H), 5.88 (s, 2H),4.59-4.55 (m, H), 4.0-3.95 (m, 1H), 3.86-3.75 (m, 2H), 3.66-3.62 (m,1H), 2.39-2.29 (m, 1H), 2.13-2.07 (m, 1H).

LC/MS (m/z) [M+1]⁺ 602.2 (calculated for C₂₅H₁₈ClF₆N₅O₂S, 601.95).

Example 1174-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazin-1-yl)-aceticacid

(4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazin-1-yl)-aceticacid was prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand piperazin-1-yl-acetic acid following General Procedure B.

¹H NMR (400 MHz, DMSO) δ 8.32 (s, 1H), 8.14 (s, 2H), 7.89 (d, 1H),7.80-7.77 (m, 2H), 7.71-7.64 (m, 2H), 6.78-6.75 (d, 1H), 5.87 (s, 2H),3.97 (br s, 2H), 3.72 (br s, 2H), 3.4 (br s, 2H), 2.84-2.80 (m, 4H).

LC/MS (m/z) [M+1]⁺ 564.2 (calculated for C₂₅H₂₁ClF₃N₅O₃S, 563.98).

Example 1181-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-[1,4]diazepan-5-one

1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-[1,4]diazepan-5-onewas prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand [1,4]diazepan-5-one following General Procedure B.

¹H NMR (400 MHz, DMSO) δ 8.36 (d, 1H), 8.16 (s, 1H), 8.12 (s, 1H), 7.97(d, 1H), 7.88-7.780 (m, 3H), 7.72-7.68 (m, 1H), 6.92 (d, 1H), 5.98 (s,2H), 4.08-4.05 (m, 2H), 3.84-3.78 (m, 2H), 3.39-3.31 (m, 2H), 2.71-2.62(m, 2H).

LC/MS (m/z) [M+1]⁺ 568.1 (calculated for C₂₅H₁₉F₆N₅O₂S, 567.51).

Example 1194-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazin-1-yl)-aceticacid

(4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazin-1-yl)-aceticacid was prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand piperazin-1-yl-acetic acid following General Procedure B.

¹H NMR (400 MHz, DMSO) δ 8.36 (s, 1H), 8.16 (s, 1H), 8.12 (s, 1H), 7.98(d, 1H), 7.84-7.81 (m, 2H), 7.70 (dd, 1H), 6.92 (d, 1H), 5.99 (s, 2H),4.10-3.99 (m, 2H), 3.84-3.82 (m, 2H), 3.65-3.50 (m, 4H), 3.10-3.05 (brs, 2H).

LC/MS (m/z) [M+1]+598.2 (calculated for C₂₆H₂₁F₆N₅O₃S, 597.53).

Example 120N—(1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidin-4-yl)-methanesulfonamide

N—(1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidin-4-yl)-methanesulfonamidewas prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand N-piperidin-4-yl-methanesulfonamide following General Procedure B.

¹H NMR (400 MHz, DMSO) δ 8.33 (s, 1H), 8.14-8.10 (m, 2H), 7.96 (d, 1H),7.79-7.77 (m, 2H), 7.69 (dd, 1H), 7.28 (d, 1H), 6.92 (d, 1H), 5.99 (s,2H), 4.44-4.41 (m, 1H), 3.84-3.81 (m, 1H), 3.58-3.43 (m, 3H), 2.95 (s,3H), 2.07-1.97 (m, 2H), 1.55-1.47 (m, 2H).

LC/MS (m/z) [M+1]⁺ 632.2 (calculated for C₂₆H₂₃F₆N₅O₃S₂, 631.62).

Example 1215-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-cyclopropyl-piperazin-1-yl)-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-cyclopropyl-piperazin-1-yl)-thiazol-4-onewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand 1-cyclopropyl-piperazine following General Procedure B.

¹H NMR (400 MHz, CDCl₃) δ 8.19 (s, 1H), 7.97 (s, 1H), 7.93 (s, 1H), 7.71(d, 1H), 7.54 (dd, 1H), 7.34-7.30 (m, 2H), 6.65 (d, 1H), 5.79 (s, 2H),4.06-4.03 (m, 2H), 3.61-3.59 (m, 2H), 2.79-2.73 (m, 4H), 1.73-1.68 (m,1H), 0.55-0.51 (m, 2H), 0.49-0.44 (m, 2H).

LC/MS (m/z) [M+1]⁺ 546.2 (calculated for C₂₆H₂₃ClF₃N₅OS, 546.01).

Example 1225-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-cyclopropyl-piperazin-1-yl)-thiazol-4-one

5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-cyclopropyl-piperazin-1-yl)-thiazol-4-onemethanesulfonamide was prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand 1-cyclopropyl-piperazine following General Procedure B.

¹H NMR (400 MHz, CDCl₃) δ 8.21 (s, 1H), 7.99 br (s, 2H), 7.93 (s, 1H),7.62 (d, 1H), 7.56 (dd, 1H), 7.32-1.30 (m, 1H), 6.81 (d, 1H), 5.88 (s,2H), 4.06-4.03 (m, 2H), 3.61-3.59 (m, 2H), 2.79-2.74 (m, 4H), 1.73-1.69(m, 1H), 0.55-0.50 (m, 2H), 0.49-0.46 (m, 2H).

LC/MS (m/z) [M+1]⁺ 580.2 (calculated for C₂₇H₂₃F₆N₅OS, 579.56).

Example 1235-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-ethyl-piperazin-1-yl)-thiazol-4-one

A.4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-ethyl-piperazine-1-carboxylicacid tert-butyl ester.

4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-ethyl-piperazine-1-carboxylicacid tert-butyl ester was prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand 2-ethyl-piperazine-1-carboxylic acid tert-butyl ester followingGeneral Procedure B.

¹H NMR (400 MHz, CD₃OD) δ 8.21 (s, 1H), 8.05 (s, 1H), 7.82 (s, 1H), 7.78(s, 1H), 7.62-7.59 (m, 1H), 7.53-7.45 (m, 2H), 6.67 (d, 1H), 5.82 (s,2H), 4.67-4.64 (m, 1H), 4.30-4.21 (m, 1H), 4.13-4.05 (m, 1H), 3.88-3.65(m, 2H), 3.56-3.43 (m, 1H), 3.19-3.12 (m, 1H), 1.62-1.56 (m, 2H), 1.49(br s, 9H), 0.92 (t, 3H).

LC/MS (m/z) [M+1]⁺ 634.0 (calculated for C₃₀H₃₁ClF₃N₅O₃S, 634.11).

B.5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-ethyl-piperazin-1-yl)-thiazol-4-onewas prepared from4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-ethyl-piperazine-1-carboxylicacid tert-butyl ester following General Procedure I.

¹H NMR (400 MHz, DMSO) δ 8.33 (s, 1H), 8.15 (s, 1H), 7.89 (d, 1H), 7.86(s, 1H), 7.81-7.78 (m, 1H), 7.71-7.65 (m, 2H), 6.81-6.78 (m, 1H), 5.87(s, 2H), 4.68-4.62 (m, 1H), 4.03-3.98 (m, 1H), 3.77-3.71 (m, 1H),3.62-3.25 (m, 4H), 1.71-1.63 (m, 2H), 1.03-0.97 (m, 3H).

LC/MS (m/z) [M+1]⁺ 534.2 (calculated for C₂₅H₂₃ClF₃N₅OS, 534.0).

Example 1245-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-ethyl-piperazin-1-yl)-thiazol-4-one

A.4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-ethyl-piperazine-1-carboxylicacid tert-butyl ester.

4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-ethyl-piperazine-1-carboxylicacid tert-butyl ester was prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand 2-ethyl-piperazine-1-carboxylic acid tert-butyl ester followingGeneral Procedure B.

¹H NMR (400 MHz, CD₃OD) δ 8.23 (d, 1H), 8.06-8.04 (m, 2H), 7.82 (s, 1H),7.77 (d, 1H), 7.64-7.59 (m, 1H), 7.55-7.53 (m, 1H), 6.85 (d, 1H), 5.93(s, 2H), 4.67-4.64 (m, 1H), 4.30-4.23 (m, 1H), 4.13-4.04 (m, 1H),3.88-3.65 (m, 2H), 3.56-3.42 (m, 1H), 3.19-3.12 (m, 1H), 1.62-1.56 (m,2H), 1.49 (br s, 9H), 0.92 (t, 3H).

LC/MS (m/z) [M+1]+667.9 (calculated for C₃₁H₃₁F₆N₅O₃S, 667.67).

B.5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-ethyl-piperazin-1-yl)thiazol-4-onewas prepared from4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-ethyl-piperazine-1-carboxylicacid tert-butyl ester following General Procedure I.

¹H NMR (400 MHz, DMSO) δ 8.36 (s, 1H), 8.17 (s, 1H), 8.13 (s, 1H), 7.98(d, 1H), 7.87 (s, 1H), 7.84-7.81 (m, 1H), 7.73-7.70 (m, 1H), 6.96-6.93(m, 1H), 5.99 (s, 2H), 4.68-4.62 (m, 1H), 4.03-3.99 (m, 1H), 3.77-3.71(m, 1H), 3.62-3.25 (m, 4H), 1.71-1.62 (m, 2H), 1.03-0.97 (m, 3H).

LC/MS (m/z) [M+1]⁺ 568.2 (calculated for C₂₆H₂₃F₆N₅OS, 567.55).

Example 1255-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(6-hydroxy-[1,4]diazepan-1-yl)-thiazol-4-one

A.5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-onewas prepared from1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehydefollowing General Procedure B.

¹H NMR (400 MHz, CDCl₃) δ 8.21 (s, 1H), 7.99-7.98 (m, 2H), 7.71 (d, 1H),7.53 (dd, 1H), 7.35-7.32 (m, 2H), 6.66 (d, 1H), 5.79 (s, 2H), 3.42 (t,2H), 1.91-1.82 (m, 2H), 1.07 (t, 3H).

LC/MS (m/z) [M+1]⁺ 496.1 (calculated for C₂₂H₁₇ClF₃N₃OS₂, 495.97).

B.5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(6-hydroxy-[1,4]diazepan-1-yl)-thiazol-4-one.5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(6-hydroxy-[1,4]diazepan-1-yl)-thiazol-4-onewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-oneand [1,4]diazepan-6-ol following General Procedure B.

¹H NMR (400 MHz, CDCl₃) δ 8.19 (s, 1H), 7.98 (s, 1H), 7.93 (d, 1H), 7.71(s, 1H), 7.54 (dd, 1H), 7.35-7.27 (m, 2H), 6.68-6.64 (m, 1H), 5.79 (s,2H), 4.29-4.07 (m, 2H), 3.95-3.77 (m, 2H), 3.70-3.64 (m, 1H), 3.35-3.31(m, 1H), 3.17-2.87 (m, 4H).

LC/MS (m/z) [M+1]⁺ 536.2 (calculated for C₂₄H₂₁ClF₃N₅O₂S, 535.97).

Example 1265-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-isoxazolidin-2-yl-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-isoxazolidin-2-yl-thiazol-4-onewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand isoxazolidine following General Procedure B.

¹H NMR (400 MHz, DMSO) δ 8.35 (s, 1H), 8.14 (s, 1H), 7.89 (d, 1H), 7.82(s, 1H), 7.78-7.76 (m, 1H), 7.70-7.64 (m, 2H), 6.74 (d, 1H), 5.86 (s,2H), 4.27 (t, 2H), 4.03 (t, 2H), 2.52-2.45 (m, 2H).

LC/MS (m/z) [M+1]⁺ 493.0 (calculated for C₂₂H₁₆ClF₃N₄O₂S, 492.9).

Example 1274-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazin-1-yl)-aceticacid ethyl ester

(4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazin-1-yl)-aceticacid ethyl ester was prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand piperazin-1-yl-acetic acid ethyl ester following General ProcedureB.

¹H NMR (400 MHz, DMSO) δ 8.32 (s, 1H), 8.14 (s, 1H), 7.89 (d, 1H), 7.82(s, 1H), 7.79-7.77 (m, 1H), 7.70-7.65 (m, 2H), 6.77 (d, 1H), 5.86 (s,2H), 4.15 (q, 2H), 4.03 (br s, 2H), 3.79-3.66 (m, 4H), 3.04-2.90 (m,4H), 1.22 (t, 3H).

LC/MS (m/z) [M+1]⁺ 592.2 (calculated for C₂₇H₂₅ClF₃N₅O₃S, 592.03).

Example 1284-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-[1,4]diazepane-1-carboxylicacid ethyl ester

A. 2-Methylsulfanyl-thiazol-4-one was prepared following GeneralProcedure E.

¹H NMR (400 MHz, CDCl₃) δ4.0 (s, 2H), 2.75 (s, 3H) (compound described:J. Heterocyclic Chem. 2002 39 1153).

B. 2-[1,4]-Diazepan-1-yl-thiazol-4-one was prepared from2-Methylsulfanyl-thiazol-4-one and [1,4]diazepane following GeneralProcedure E

¹H NMR (400 MHz, CDCl₃) δ4.01-3.94 (m, 4H), 3.68-3.65 (m, 1H), 3.61-3.58(m, 1H), 3.09-3.07 (m, 1H), 3.05-3.02 (m, 1H), 2.94-2.89 (m, 2H),1.99-1.88 (m, 2H), 1.71 (br s, 1H).

LC/MS (m/z) [M+1]⁺ 200.2 (calculated for C₈H₁₃N₃OS, 199.27).

C. 4-(4-Oxo-4,5-dihydro-thiazol-2-yl)-[1,4]diazepane-1-carboxylic acidethyl ester.

To a solution of 2-[1,4]diazepan-1-yl-thiazol-4-one (105 mg, 0.52 mmol)in dichloromethane (8 mL) was added ethyl chloroformate (68 mg, 0.63mmol) followed by triethylamine (64 mg, 0.63 mmol). The reaction mixturewas stirred at room temperature for 4 hours and partitioned betweensaturated aqueous hydrogencarbonate solution and dichloromethane. Thedichloromethane layer was washed with brine, dried over Na₂SO₄,filtered, and the solvent evaporated in vacuo to yield a crude solid.The crude solid was purified via flash chromatography (2.5% methanol indichloromethane) to yield the title compound (125 mg, 88%).

¹H NMR (400 MHz, CDCl₃) δ4.19-4.14 (m, 2H), 4.00-3.89 (m, 4H), 3.67-3.61(m, 4H), 3.53-3.44 (m, 2H), 2.06-1.98 (m, 2H), 1.27 (t, 3H).

LC/MS (m/z) [M+1]⁺ 272.1 (calculated for C₁₁H₁₇N₃O₃S, 271.34).

D.4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-[1,4]diazepane-1-carboxylicacid ethyl ester.

4-(4-oxo-4,5-dihydro-thiazol-2-yl)-[1,4]diazepane-1-carboxylic acidethyl ester was prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehydefollowing General Procedure E.

¹H NMR (400 MHz, CDCl₃) δ 8.20 (s, 1H), 7.97-7.94 (m, 2H), 7.71 (d, 1H),7.55-7.53 (m, 1H), 7.35-7.31 (m, 2H), 6.66 (d, 1H), 5.79 (s, 2H),4.19-3.99 (m, 4H), 3.78-3.68 (m, 4H), 3.57-3.47 (m, 2H), 2.12-2.04 (m,2H), 1.27 (q, 3H).

LC/MS (m/z) [M+1]⁺ 592.2 (calculated for C₂₇H₂₅ClF₃N₅O₃S, 592.03).

Example 1294-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-[1,4]diazepane-1-carboxylicacid ethyl ester

4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-[1,4]diazepane-1-carboxylicacid ethyl ester was prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehydefollowing General Procedure E.

¹H NMR (400 MHz, CDCl₃) δ 8.22 (s, 1H), 7.98 (br s, 2H), 7.96-7.94 (m,1H), 7.57-7.54 (m, 1H), 7.34-7.31 (m, 1H), 6.82 (d, 1H), 5.89 (s, 2H),4.19-4.00 (m, 4H), 3.78-3.68 (m, 4H), 3.57-3.47 (m, 2H), 2.12-2.04 (m,2H), 1.26 (q, 3H).

LC/MS (m/z) [M+1]⁺ 526.2 (calculated for C₂₈H₂₅F₆N₅O₃S, 625.59).

Example 1301-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}piperidin-4-yloxy)-aceticacid methyl ester

(1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}piperidin-4-yloxy)-aceticacid methyl ester was prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand (piperidin-4-yloxy)-acetic acid methyl ester following GeneralProcedure B.

¹H NMR (400 MHz, CDCl₃) δ 8.19 (s, 1H), 7.97 (s, 1H), 7.93 (s, 1H), 7.71(d, 1H), 7.54 (dd, 1H), 7.34-7.29 (m, 2H), 6.65 (d, 1H), 5.79 (s, 2H),4.23-4.17 (m, 3H), 4.13-4.05 (m, 1H), 3.89-3.80 (m, 2H), 3.78 (s, 3H),3.57-3.48 (m, 1H), 2.01-1.88 (m, 4H).

LC/MS (m/z) [M+1]⁺ 593.2 (calculated for C₂₇H₂₄ClF₃N₄O₄S, 593.02).

Example 1311-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidin-4-yloxy)-aceticacid

A solution of(1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidin-4-yloxy)-aceticacid methyl ester (0.043 g, 0.072 mmol) in THF/methanol (3 mL, 2/1) wastreated with an aqueous solution of lithium hydroxide (1 mL, 6.9 mg,0.29 mmol) and stirred at room temperature for 1 hour. The reactionmixture was concentrated and acidified with aqueous 0.3 mM HCl. Theprecipitate obtained was washed with water, dried and purified usingsemi-preparative reverse phase HPLC (YMC ODS A, 100×30 mm, 50 μM I.D.,0.05% TFA acetonitrile/0.05% TFA water=30/70 to 100/0) to yield thetitle compound as a flocculent solid.

¹H NMR (400 MHz, DMSO) δ 8.32 (s, 1H), 8.14 (s, 1H), 7.89 (s, 1H),7.78-7.76 (m, 2H), 7.71-7.65 (m, 2H), 6.76 (d, 1H), 5.87 (s, 2H), 4.12(s, 2H), 4.10-4.06 (m, 1H), 3.82-5.53 (m, 4H), 2.02-1.93 (m, 2H),1.72-1.63 (m, 2H).

LC/MS (m/z) [M+1]⁺ 579.2 (calculated for C₂₆H₂₂ClF₃N₄O₄S, 578.99).

Example 1325-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one

A.4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester was prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 2-Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl esterfollowing General Procedure B.

LC/MS (m/z) [M+1]⁺ 636.0 (calculated for C₂₉H₂₉ClF₃N₅O₄S, 636.09).

B.5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-onewas prepared from4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester following General Procedure I.

¹H NMR (400 MHz, DMSO) δ 8.33 (s, 1H), 8.15 (s, 1H), 7.89 (s, 1H), 7.86(s, 1H), 7.79 (dd, 1H), 7.71-7.65 (m, 2H), 6.80 (dd, 1H), 5.87 (s, 2H),5.63 (br s, 1H), 4.73-4.66 (m, 1H), 4.06-4.00 (m, 1H), 3.75-3.63 (m,4H), 3.59-3.34 (m, 3H).

LC/MS (m/z) [M+1]⁺ 536.2 (calculated for C₂₄H₂₁ClF₃N₅O₂S, 535.97).

Example 1335-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-[(2-fluoro-ethyl)-[1,4]diazepan-1-yl]-thiazol-4-one

A.5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[1,4]diazepan-1-yl-thiazol-4-one.5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[1,4]diazepan-1-yl-thiazol-4-onewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand [1,4]diazepane following General Procedure D.

¹H NMR (400 MHz, CDCl₃) δ 8.19 (dd, 1H), 7.97 (s, 1H), 7.92 (s, 1H),7.71 (s, 1H), 7.56-7.53 (m, 1H), 7.34-7.26 (m, 2H), 6.65 (d, 1H), 5.79(s, 2H), 4.10-4.05 (m, 2H), 3.80-3.77 (m, 1H), 3.72-3.69 (m, 1H),3.15-3.12 (m, 1H), 3.10-3.08 (m, 1H), 2.96-2.92 (m, 2H), 2.05-1.95 (m,2H).

LC/MS (m/z) [M+1]⁺ 520.3 (calculated for C₂₄H₂₁ClF₃N₅OS, 519.97).

B.5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-fluoro-ethyl)-[1,4]diazepan-1-yl]-thiazol-4-one.

A solution5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[1,4]diazepan-1-yl-thiazol-4-one(0.016 g, 0.03 mmol) in acetonitrile (1.5 mL) was treated with potassiumcarbonate (0.022 g, 0.15 mmol) and 1-bromo-2-fluoro-ethane (0.04 g, 0.3mmol). Reaction mixture was stirred at 70° C. for 18 hours and thesolvent evaporated in vacuo. The residue was partitioned betweendichloromethane and water. The dichloromethane layer was washed withbrine, dried over Na₂SO₄, filtered, and the solvent evaporated in vacuoto yield a crude solid. The crude solid was purified via flashchromatography (5% methanol in dichloromethane) to yield the titlecompound (17 mg, 100%).

¹H NMR (400 MHz, CDCl₃) δ 8.19 (s, 1H), 7.98 (s, 1H), 7.93 (s, 1H), 7.71(s, 1H), 7.56-7.54 (m, 1H), 7.34-7.30 (m, 2H), 6.65 (d, 1H), 5.79 (s,2H), 4.63-4.58 (m, 1H), 4.51-4.46 (m, 1H), 4.12-4.06 (m, 2H), 3.76-3.73(m, 2H), 3.04-3.02 (m, 1H), 2.95-2.90 (m, 2H), 2.88-2.79 (m, 3H),2.11-1.98 (m, 2H).

LC/MS (m/z) [M+1]⁺ 566.2 (calculated for C₂₆H₂₄ClF₄N₅OS, 566.01).

Example 1345-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methanesulfonyl-[1,4]diazepan-1-yl)-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methanesulfonyl-[1,4]diazepan-1-yl)-thiazol-4-onewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[1,4]diazepan-1-yl-thiazol-4-oneand methane sulfonyl chloride according to Example 133.

¹H NMR (400 MHz, CDCl₃) δ 8.20 (dd, 1H), 7.97-7.95 (m, 2H), 7.71 (s,1H), 7.55-7.52 (m, 1H), 7.35-7.31 (m, 2H), 6.67 (d, 1H), 5.79 (s, 2H),4.19-4.12 (m, 2H), 3.90-3.87 (m, 1H), 3.84-3.82 (m, 1H), 3.64-3.62 (m,1H), 3.57-3.55 (m, 1H), 3.43-3.39 (m, 2H), 2.89 (d, 3H), 2.22-2.16 (m,2H).

LC/MS (m/z) [M+1]⁺ 598.2 (calculated for C₂₅H₂₃ClF₃N₅O₃S₂, 598.06).

Example 1355-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2,2,2-trifluoro-ethyl)-[1,4]diazepan-1-yl]-thiazol-4-one

A solution of5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[1,4]diazepan-1-yl-thiazol-4-one(0.051 g, 0.098 mmol) in DMSO (2.2 mL) was treated with potassiumcarbonate (0.045 g, 0.32 mmol) and methanesulfonic acid2,2,2-trifluoro-ethyl ester (0.06 g, 0.32 mmol). Reaction mixture wasstirred at 70° C. for 1 hour and partitioned between dichloromethane andwater. The dichloromethane layer was dried over Na₂SO₄, filtered, andthe solvent evaporated in vacuo to yield a crude solid. The crude solidwas purified using semi-preparative reverse phase HPLC (YMC ODS A,100×30 mm, 50 μM I.D., 0.05% TFA acetonitrile/0.05% TFA water=30/70 to100/0) to yield the title compound as a flocculent solid.

¹H NMR (400 MHz, CD₃OD) δ 8.25 (s, 1H), 8.11 (s, 1H), 7.86 (s, 1H), 7.79(d, 1H), 7.66 (dd, 1H), 7.56 (d, 1H), 7.48 (dd, 1H), 6.68 (d, 1H), 5.86(s, 2H), 4.05-4.0 (m, 2H), 3.85-3.79 (m, 2H), 3.36-3.30 (m, 2H),3.20-3.18 (m, 1H), 3.14-3.11 (m, 1H), 3.0-2.96 (m, 2H), 2.06-2.01 (m,1H), 2.0-1.92 (m, 1H).

LC/MS (m/z) [M+1]⁺ 602.3 (calculated for C₂₆H₂₂ClF₆N₅OS, 602.0).

Example 1364-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}[1,4]diazepane-1-carboxylicacid 2,2,2-trifluoro-ethyl ester

4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-[1,4]diazepane-1-carboxylicacid 2,2,2-trifluoro-ethyl ester was prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[1,4]diazepan-1-yl-thiazol-4-oneand 2,2,2-Trifluoroethyl chloroformate according to Example 133.

¹H NMR (400 MHz, CD₃OD) δ 8.24 (s, 1H), 8.08 (s, 1H), 7.85 (s, 1H), 7.79(s, 1H), 7.65-7.62 (m, 1H), 7.55-7.53 (m, 1H), 7.48-7.46 (m, 1H), 6.67(d, 1H), 5.84 (s, 2H), 4.64-4.57 (m, 2H), 4.11-4.08 (m, 1H), 4.02 (br s,1H), 3.89-3.75 (m, 4H), 3.63-3.57 (m, 2H), 2.03-1.93 (m, 2H).

LC/MS (m/z) [M+1]⁺ 646.3 (calculated for C₂₇H₂₂ClF₆N₅O₃S, 646.0).

Example 1371-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-pyrrolidine-3-carboxylicacid

1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-pyrrolidine-3-carboxylicacid was prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand pyrrolidine-3-carboxylic acid following General Procedure B.

¹H NMR (400 MHz, DMSO) δ 8.34 (s, 1H), 8.14-8.12 (m, 1H), 7.89 (d, 1H),7.79-7.76 (m, 2H), 7.71-7.64 (m, 2H), 6.75 (d, 1H), 5.86 (s, 2H),3.93-3.66 (m, 4H), 3.37-3.27 (m, 1H), 2.36-2.18 (m, 2H).

LC/MS (m/z) [M+1]⁺ 535.2 (calculated for C₂₄H₁₈ClF₃N₄O₃S, 534.94).

Example 1382-[4-(2-Amino-acetyl)-[1,4]diazepan-1-yl]-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one

A.[2-(4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-[1,4]diazepan-1-yl)-2-oxo-ethyl]-carbamicacid tert-butyl ester.

A solution5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[1,4]diazepan-1-yl-thiazol-4-one(0.026 g, 0.05 mmol) and tert-butoxycarbonylamino-acetic acid (0.0087 g,0.05 mmol) in dichloromethane (3 mL) was treated with EDCI (0.0104 g,0.055 mmol) and triethylamine (0.006 g, 0.06 mmol). Reaction mixture wasstirred at room temperature for 18 hours and was then partitionedbetween dichloromethane and an aqueous saturated hydrogencarbonatesolution. The dichloromethane layer was then washed with aqueous 10%citric acid, brine, dried over Na₂SO₄, filtered, and the solventevaporated in vacuo to yield a crude solid. The crude solid was purifiedvia flash chromatography (5% methanol in dichloromethane) to yield thetitle compound (26 mg, 77%).

¹H NMR (400 MHz, CDCl₃) δ 8.20 (s, 1H), 7.96-7.94 (m, 2H), 7.71 (s, 1H),7.55-7.52 (m, 1H), 7.35-7.30 (m, 2H), 6.66 (dd, 1H), 5.79 (s, 2H), 5.36(br s, 1H), 4.16-4.05 (m, 2H), 4.03-3.96 (m, 2H), 3.89-3.62 (m, 4H),3.55-3.50 (m, 2H), 2.18-2.07 (m, 2H), 1.44 (s, 9H).

LC/MS (m/z) [M+1]+676.7 (calculated for C₃₁H₃₂ClF₃N₆O₄S, 677.14).

B.2-[4-(2-Amino-acetyl)-[1,4]diazepan-1-yl]-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one.

2-[4-(2-Amino-acetyl)-[1,4]diazepan-1-yl]-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-onewas prepared from[2-(4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-[1,4]diazepan-1-yl)-2-oxo-ethyl]-carbamicacid tert-butyl ester following General Procedure I.

¹H NMR (400 MHz, CD₃OD) δ 8.25-8.22 (m, 1H), 8.18-8.09 (m, 1H), 7.89 (s,1H), 7.80 (s, 1H), 7.66-7.63 (m, 1H), 7.58-7.55 (m, 1H), 7.48 (dd, 1H),6.71-6.69 (m, 1H), 5.85 (s, 2H), 4.19-4.09 (m, 2H), 4.0-3.86 (m, 5H),3.80-3.75 (m, 2H), 3.64-3.59 (m, 1H), 2.03-1.95 (m, 2H).

LC/MS (m/z) [M+1]⁺ 577.2 (calculated for C₂₆H₂₄ClF₃N₆O₂S, 577.02).

Example 1395-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one

A.4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester was prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand (2R)—Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl esterfollowing General Procedure C.

LC/MS: mass calcd. for C₃₀H₂₉F₆N₅O₄S: 669.18, found 670.3 [M+H]⁺.

B.5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-hydroxymethyl-piperazin-1-yl)thiazol-4-onewas prepared from4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester following General Procedure I.

¹H NMR (400 MHZ, CDCl₃): δ 8.22 (dd, 1H), 7.99 (br, 2H), 7.94 (s, 1H),7.63 (d, 1H), 7.56 (m, 1H), 7.32 (d, 1H), 6.82 (d, 1H), 5.88 (s, 2H),4.77 (m, 1H), 3.78-3.72 (2H), 3.70-3.55 (1H), 3.53-3.15 (3H), 3.05-2.92(2H), 2.01 (br, 1H).

LC/MS: mass calcd. for C₂₅H₂₁F₆N₅O₂S: 569.13, found 570.5 [M+H]⁺.

Example 1405-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-((2S)-hydroxymethyl-morpholin-4-yl)-thiazol-4-one

5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-((2S)-hydroxymethyl-morpholin-4-yl)-thiazol-4-onewas prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand (2S)-Morpholin-2-yl-methanol following General Procedure C.

¹H NMR (400 MHZ, CDCl₃): δ 8.22 (d, 1H), 7.99 (br, 2H), 7.96 (s, 1H),7.63 (d, 1H), 7.55 (m, 1H), 7.32 (d, 1H), 6.82 (d, 1H), 5.89 (s, 2H),4.81 (m, 1H), 4.11 (m, 1H), 3.84-3.25 (9H).

LC/MS: mass calcd. for C₂₅H₂₀F₆N₄O₃S: 570.12, found 571.4 [M+H]⁺.

Example 1415-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3(R)-hydroxymethyl-morpholin-4-yl)-thiazol-4-one

5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-((2S)-hydroxymethyl-morpholin-4-yl)-thiazol-4-onewas prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand (3R)-Morpholin-3-yl-methanol following General Procedure C.

¹H NMR (400 MHZ, CDCl₃): δ 8.21-8.20 (1H), 7.98-7.96 (2H), 7.96-7.92(1H), 7.65-7.60 (1H), 7.56-7.51 (1H), 7.33-7.30 (1H), 6.82 (m, 1H),5.88-5.86 (2H), 4.92-4.70 (1H), 4.16-3.97 (4H), 3.86-3.50 (4H),2.42-2.14 (1H).

LC/MS: mass calcd. for C₂₅H₂₀F₆N₄O₃S: 570.12, found 571.4 [M+H]⁺.

Example 1425-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3(R)-hydroxymethyl-morpholin-4-yl)-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3(R)-hydroxymethyl-morpholin-4-yl)-thiazol-4-onewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand (3R)-Morpholin-3-yl-methanol following General Procedure C.

¹H NMR (400 MHZ, CDCl₃): δ 8.19 (s, 1H), 7.97 (d, 1H), 7.95 (d, 1H),7.71 (d, 1H), 7.53 (m, 1H), 7.36-7.28 (2H), 6.66 (m, 1H), 5.79 (d, 2H),4.92-3.49 (9H).

LC/MS: mass calcd. for C₂₄H₂₀ClF₃N₄O₃S: 536.09, found 537.5 [M+H]⁺.

Example 1435-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[2(S)-(tert-butoxymethyl)morpholin-4-yl]-1,3-thiazol-4(5H)-one

5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[2(S)-(tert-butoxymethyl)morpholin-4-yl]-1,3-thiazol-4(5H)-onewas obtained as a side-product during the synthesis of5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-((2S)-hydroxymethyl-morpholin-4-yl)-thiazol-4-one(see example 140).

¹H NMR (400 MHz, CDCl₃) δ 8.22 (d, 1H), 8.00-7.95 (m, 3H), 7.63 (d, 1H),7.56 (m, 1H), 7.33 (m, 1H), 6.82 (d, 1H), 5.89 (s, 2H), 4.87-4.74 (m,1H), 4.16-3.24 (m, 9H), 1.22 (d, 9H).

LC/MS (m/z) [M+1]⁺ 627.0 (calculated for C₂₉H₂₈F₆N₄O₃S, 626.2).

Example 1445-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-hexahydro-furo[3,4-c]pyrrol-1-one

5-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-hexahydro-furo[3,4-c]pyrrol-1-onewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-oneand hexahydro-furo[3,4-c]pyrrol-1-one following General Procedure B.

¹H NMR (400 MHz, DMSO) δ 8.34 (s, 1H), 8.14-8.12 (m, 1H), 7.88 (d, 1H),7.80-7.76 (m, 2H), 7.7-7.64 (m, 2H), 6.76 (d, 1H), 5.86 (s, 2H),4.5-4.45 (m, 1H), 4.37-4.33 (m, 1H), 4.19-4.14 (m, 0.5H), 4.1-3.98 (m,2H), 3.91-3.88 (m, 0.5H), 3.7-3.59 (m, 2H), 3.51-3.41 (m, 1H).

LC/MS (m/z) [M+1]⁺ 547.2 (calculated for C₂₅H₁₈ClF₃N₄O₃S, 546.07).

Example 145(1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-pyrrolidin-3-yl]-aceticacid

(1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-pyrrolidin-3-yl)-aceticacid was prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-oneand pyrrolidin-3-yl-acetic acid following General Procedure B.

¹H NMR (400 MHz, DMSO) δ 8.35 (d, 1H), 8.12 (d, 1H), 7.89 (d, 1H),7.72-7.82 (m, 2H), 7.61-7.72 (m, 2H), 6.75 (d, 1H), 5.86 (s, 2H), 3.98(dd, 0.5H), 3.89-3.85 (m, 1H), 3.77-3.71 (m, 0.5H), 3.69-3.62 (m, 1H),3.39-3.33 (m, 1H), 2.66 (td, 1H), 2.48-2.45 (m, 1H), 2.25-2.16 (m, 1H),1.84-1.65 (m, 1H).

LC/MS (m/z) [M+1]⁺ 549.2 (calculated for C₂₅H₂₀ClF₃N₄O₃S, 548.09).

Example 1465-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(1,1-dioxidothiomorpholin-4-yl)-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(1,1-dioxidothiomorpholin-4-yl)-thiazol-4-onewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-oneand thiomorpholine 1,1-dioxide following General Procedure B.

¹H NMR (400 MHz, DMSO) δ 8.33 (d, 1H), 8.16 (d, 1H), 7.89 (d, 1H), 7.86(s, 1H), 7.80-7.77 (m, 1H), 7.71 (dd, 1H), 7.66 (dd, 1H), 6.78 (d, 1H),5.87 (s, 2H), 4.34-4.31 (m, 2H), 4.09-4.07 (m, 2H), 3.47-3.45 (m, 2H),3.42-3.39 (m, 2H).

LC/MS (m/z) [M+1]⁺ 555.2 (calculated for C₂₃H₁₈ClF₃N₄O₃S₂, 554.05).

Example 1475-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(3,5-dimethyl-[1,2,4]triazol-4-yl)-piperidin-1-yl]-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(3,5-dimethyl-[1,2,4]triazol-4-yl)-piperidin-1-yl]-thiazol-4-onewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-oneand 4-(3,5-Dimethyl-[1,2,4]triazol-4-yl)piperidine following GeneralProcedure B.

¹H NMR (400 MHz, DMSO) δ 8.32 (d, 1H), 8.15 (d, 1H), 7.89 (d, 1H), 7.81(s, 1H), 7.78-7.76 (m, 1H), 7.71 (dd, 1H), 7.66 (dd, 1H), 6.77 (d, 1H),5.87 (s, 2H), 4.81-4.77 (m, 1H), 4.48-4.42 (m, 1H), 4.01-3.98 (m, 1H),3.70-3.64 (m, 1H), 3.42-3.12 (m, 1H), 2.4 (s, 6H).

LC/MS (m/z) [M+1]⁺ 600.2 (calculated for C₂₈H₂₅ClF₃N₇OS, 599.15).

Example 1485-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-thiomorpholin-4-yl-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-thiomorpholin-4-yl-thiazol-4-onewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-oneand thiomorpholine following General Procedure B.

¹H NMR (400 MHz, DMSO) δ 8.33 (d, 1H), 8.14 (d, 1H), 7.89 (d, 1H), 7.81(s, 1H), 7.78-7.75 (m, 1H), 7.69 (dd, 1H), 7.66 (dd, 1H), 6.77 (d, 1H),5.86 (s, 2H), 4.20-4.18 (m, 2H), 3.95-3.92 (m, 2H), 2.84-2.82 (m, 2H),2.79-2.77 (m, 2H).

LC/MS (m/z) [M+1]⁺ 523.2 (calculated for C₂₃H₁₈ClF₃N₄OS₂, 522.06).

Example 1495-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-fluoro-azetidin-1-yl)-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-fluoro-azetidin-1-yl)-thiazol-4-onewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-oneand 3-fluoro-azetidine following General Procedure B.

¹H NMR (400 MHz, DMSO) δ 8.34 (d, 1H), 8.11 (d, 1H), 7.89 (d, 1H), 7.80(s, 1H), 7.78-7.76 (m, 1H), 7.68-7.64 (m, 2H), 6.75 (d, 1H), 5.86 (s,2H), 5.70-5.67 (m, 0.5H), 5.56-5.53 (m, 0.5H), 4.72-4.62 (m, 2H),4.54-4.39 (m, 2H).

LC/MS (m/z) [M+1]⁺ 495.2 (calculated for C₂₂H₁₅ClF₄N₄OS, 494.06).

Example 1505-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-tetrazol-1-yl-piperidin-1-yl)-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-tetrazol-1-yl-piperidin-1-yl)-thiazol-4-onewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-oneand 4-tetrazol-1-yl-piperidine following General Procedure B.

¹H NMR (400 MHz, DMSO) δ 9.03 (s, 1H), 8.33 (d, 1H), 8.15 (s, 1H), 7.89(d, 1H), 7.82 (s, 1H), 7.79-7.77 (m, 1H), 7.70 (dd, 2H), 7.66 (dd, 1H),6.76 (d, 1H), 5.87 (s, 2H), 5.38-5.33 (m, 1H), 4.63-4.59 (m, 1H),4.01-3.98 (m, 1H), 3.80-3.74 (m, 1H), 3.70-3.63 (m, 1H), 2.48-2.40 (m,2H), 2.25-2.15 (m, 2H).

LC/MS (m/z) [M+1]⁺ 572.9 (calculated for C₂₅H₂₀ClF₃N₈OS, 572.11).

Example 1515-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(6-hydroxy-[1,4]diazepan-1-yl)thiazol-4-one

5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(6-hydroxy-[1,4]diazepan-1-yl)-thiazol-4-onewas prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand [1,4]Diazepan-6-ol following General Procedure B.

¹H NMR (400 MHz, CDCl₃) δ 8.21 (d, 1H), 7.98 (br s, 2H), 7.93 (d, 1H),7.62 (d, 1H), 7.55 (dd, 1H), 7.31 (dd, 1H), 6.81 (t, 1H), 5.88 (s, 2H),4.28-4.07 (m, 2.5H), 3.94-3.77 (m, 1.5H), 3.70-3.64 (m, 1H), 3.36-3.29(m. 0.5H), 3.21-2.86 (m, 3.5H).

LC/MS (m/z) [M+1]⁺ 570.2 (calculated for C₂₅H₂₁F₆N₅O₂S, 569.13).

Example 1523-[(1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carbonyl)-amino]-propionicacid methyl ester

A. 3-(2-Methoxycarbonyl-ethylcarbamoyl)-azetidine-1-carboxylic acidtert-butyl ester

A solution of azetidine-1,3-dicarboxylic acid mono-tert-butyl ester (0.4g, 1.98 mmol) and 3-amino-propionic acid methyl ester hydrochloride(0.277 g, 1.98 mmol) in dichloromethane (16 mL) and THF (6 mL) wastreated with diisopropylethylamine (0.256 g, 1.98 mmol); it was thenadded EDCI (0.42 g, 2.18 mmol) and dimethylaminopyridine (0.073 g, 0.59mmol). The reaction mixture was stirred at room temperature for 50 hoursand rotavapored to dryness. The residue was dissolved indichloromethane. The dichloromethane layer was then successively washedwith aqueous 5% citric acid, aqueous saturated hydrogencarbonatesolution, brine, dried over Na₂SO₄, filtered, and the solvent evaporatedin vacuo to yield the title compound as a gum (551 mg, 97%).

¹H NMR (400 MHz, CDCl₃) δ 6.16 (br s, 1H), 4.10-4.01 (m, 4H), 3.71 (s,3H), 3.55 (q, 2H), 3.18-3.11 (m, 1H), 2.56 (t, 2H), 1.43 (s, 9H).

LC/MS (m/z) [MNa]⁺ 309.3 (calculated for C₁₃H₂₂N₂O₅, 286.15).

B. 3-[(Azetidine-3-carbonyl)-amino]-propionic acid methyl esterhydrochloride

A solution of3-(2-Methoxycarbonyl-ethylcarbamoyl)-azetidine-1-carboxylic acidtert-butyl ester (0.55 g, 1.92 mmol) in MeOH (4 mL) and THF (2 mL) wastreated with 4.0N HCl in 1,4-dioxane (4 mL) and stirred at 0° C. for 30minutes and at room temperature for 5 hours. The solvent was removed invacuo to yield the title compound as a gum (100%).

¹H NMR (400 MHz, D₂O) δ4.05-4.03 (m, 4H), 3.51 (s, 3H), 3.45-3.43 (m,1H), 3.29 (t, 2H), 2.46 (t, 2H).

LC/MS (m/z) [M+1]⁺ 187.2 (calculated for C₈H₁₄N₂O₃, 186.10).

C.3-O-(4-oxo-4,5-dihydro-thiazol-2-yl)-azetidine-3-carbonyl)-amino]-propionicacid methyl ester was prepared from3-[(Azetidine-3-carbonyl)-amino]-propionic acid methyl ester and2-Methylsulfanyl-thiazol-4-one following General Procedure D.

¹H NMR (400 MHz, CDCl₃) δ 6.55 (br s, 1H), 4.51-4.42 (m, 3H), 4.25 (t,1H), 3.96 (s, 2H), 3.71 (s, 3H), 3.67-3.64 (m, 1H), 3.59-3.54 (m, 1H),3.53-3.45 (m, 1H), 2.58 (t, 2H).

LC/MS (m/z) [M+1]⁺ 286.1 (calculated for C₁₁H₁₅N₃O₄S, 285.08).

D.3-1(1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carbonyl)-amino]-propionicacid methyl ester was prepared from3-{[1-(4-oxo-4,5-dihydro-thiazol-2-yl)-azetidine-3-carbonyl]-amino}-propionicacid methyl ester and1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehydefollowing General Procedure D.

¹H NMR (400 MHz, CDCl₃) δ 8.21 (d, 1H), 7.93 (br s, 1H), 7.93 (d, 1H),7.84 (s, 1H), 7.50 (dd, 1H), 7.34-7.31 (m, 2H), 6.64 (d, 1H), 6.34 (brs, 1H), 5.79 (s, 2H), 4.21-4.16 (m, 1H), 3.93-3.88 (m, 1H), 3.79-3.73(m, 2H), 3.72 (s, 3H), 3.60-3.52 (m, 2H), 2.66-2.60 (m, 1H), 2.57 (t,2H).

LC/MS (m/z) [M+1]⁺ 606.2 (calculated for C₂₇H₂₃ClF₃N₅O₄S, 605.11).

Example 1533-[(1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carbonylyamino]-propionicacid methyl ester

3-[(1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carbonylyamino]-propionicacid methyl ester was prepared from3-{[1-(4-oxo-4,5-dihydro-thiazol-2-yl)-azetidine-3-carbonyl]-amino}-propionicacid methyl ester and1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde followingGeneral Procedure D.

¹H NMR (400 MHz, CDCl₃) δ 8.23 (d, 1H), 7.93 (s, 1H), 7.94 (d, 1H), 7.85(s, 1H), 7.62 (d, 1H), 7.51 (dd, 1H), 7.34 (d, 1H), 6.79 (d, 1H), 6.35(br s, 1H), 5.89 (s, 2H), 4.21-4.17 (m, 1H), 3.94-3.88 (m, 1H),3.79-3.73 (m, 2H), 3.72 (s, 3H), 3.60-3.53 (m, 2H), 2.66-2.60 (m, 1H),2.57 (t, 2H).

LC/MS (m/z) [M+1]⁺ 640.2 (calculated for C₂₈H₂₃F₆N₅O₄S, 639.14).

Example 1544-Amino-1-{5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}piperidine-4-carboxylicacid

4-Amino-1-{5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}piperidine-4-carboxylicacid was prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-oneand 4-amino-piperidine-4-carboxylic acid following General Procedure B.

¹H NMR (400 MHz, DMSO) δ 8.30 (d, 1H), 8.13 (s, 1H), 7.87 (d, 1H), 7.80(s, 1H), 7.76 (d, 1H), 7.69 (dd, 1H), 7.64 (dd, 1H), 6.75 (d, 1H), 5.85(s, 2H), 4.29-4.24 (m. 0.5H), 3.99-3.89 (m, 1H), 3.84-3.81 (m, 0.5H),3.23-3.20 (m, 2H), 2.26-2.20 (m, 2H), 1.99-1.96 (m, 2H).

LC/MS (m/z) [M+1]⁺ 564.2 (calculated for C₂₅H₂₁ClF₃N₅O₃S, 563.1).

Example 155N—(1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidin-4-yl)-N-methyl-acetamide

N—(1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidin-4-yl)-N-methyl-acetamidewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-oneand N-Methyl-N-piperidin-4-yl-acetamide following General Procedure B.

¹H NMR (400 MHz, DMSO) δ 8.18 (d, 1H), 7.97 (d, 1H), 7.93 (s, 1H), 7.71(d, 1H), 7.54 (dd, 1H), 7.34-7.30 (m, 2H), 6.66 (d, 1H), 5.79 (s, 2H),5.11-5.06 (m, 1H), 4.89-4.83 (m, 1H), 3.96-3.92 (m, 1H), 3.50 (td, 1H),2.87 (s, 3H), 2.12 (s, 3H), 1.90-1.72 (m, 4H).

LC/MS (m/z) [M+1]⁺ 576.2 (calculated for C₂₇H₂₅ClF₃N₅O₂S, 575.14).

Example 1564-Amino-1-{5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carboxylicacid ethyl ester

4-Amino-1-{5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}piperidine-4-carboxylicacid ethyl ester was prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-oneand 4-amino-piperidine-4-carboxylic acid ethyl ester following GeneralProcedure B.

¹H NMR (400 MHz, DMSO) δ 8.32 (d, 1H), 8.15 (s, 1H), 7.89 (d, 1H), 7.84(s, 1H), 7.79 (d, 1H), 7.70 (dd, 1H), 7.66 (dd, 1H), 6.78 (d, 1H), 5.87(s, 2H), 4.29 (q, 2H), 3.91-3.68 (m, 4H), 2.38-2.26 (m, 2H), 2.06-1.94(m, 2H), 1.29 (t, 3H).

LC/MS (m/z) [M+1]⁺ 592.2 (calculated for C₂₇H₂₅ClF₃N₅O₃S, 591.13).

Example 1575-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-pyrazol-1-yl-piperidin-1-yl)-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-pyrazol-1-yl-piperidin-1-yl)-thiazol-4-onewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-oneand 4-Pyrazol-1-yl-piperidine following General Procedure B.

¹H NMR (400 MHz, DMSO) δ 8.32 (d, 1H), 8.15 (t, 1H), 7.89 (d, 1H), 7.83(d, 1H), 7.81 (s, 1H), 7.77 (d, 1H), 7.71 (dd, 1H), 7.66 (dd, 1H), 7.46(dd, 1H), 6.77 (d, 1H), 6.26 (t, 1H), 5.87 (s, 2H), 4.71-4.60 (m, 2H),4.0-3.96 (m, 1H), 3.68 (td, 1H), 3.49 (td, 1H), 2.25-2.16 (m, 2H),2.08-2.00 (m, 2H).

LC/MS (m/z) [M+1]⁺ 571.2 (calculated for C₂₇H₂₂ClF₃N₆OS, 570.12).

Example 1585-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-[1,2,4]triazol-1-yl-piperidin-1-yl)-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-[1,2,4]triazol-1-yl-piperidin-1-yl)-thiazol-4-onewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-oneand 4-[1,2,4]Triazol-1-yl-piperidine following General Procedure B.

¹H NMR (400 MHz, DMSO) δ 8.63 (s, 1H), 8.33 (d, 1H), 8.15 (br s, 1H),8.0 (s, 1H), 7.89 (d, 1H), 7.81 (s, 1H), 7.77 (d, 1H), 7.70 (dd, 1H),7.66 (dd, 1H), 6.77 (d, 1H), 5.87 (s, 2H), 4.78-4.67 (m, 2H), 4.01-3.97(m, 1H), 3.69 (td, 1H), 3.50 (td, 1H), 2.33-2.22 (m, 2H), 2.09-2.02 (m,2H).

LC/MS (m/z) [M+1]⁺ 572.2 (calculated for C₂₆H₂₁ClF₃N₇OS, 571.12).

Example 1595-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-imidazol-1-yl-piperidin-1-yl)-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-imidazol-1-yl-piperidin-1-yl)-thiazol-4-onewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-oneand 4-Imidazol-1-yl-piperidine following General Procedure B.

¹H NMR (400 MHz, CDCl₃) δ 8.16 (d, 1H), 7.97 (m, 1H), 7.96 (s, 1H), 7.71(d, 1H), 7.62 (br s, 1H), 7.54 (dd, 1H), 7.35-7.30 (m, 2H), 7.14 (br s1H), 7.03 (br s, 1H), 6.67 (d, 1H), 5.79 (s, 2H), 5.17-5.13 (m, 1H),4.39-4.33 (m, 1H), 4.06-4.02 (m, 1H), 3.55 (td, 1H), 3.31 (td, 1H),2.37-2.28 (m, 2H), 2.12-2.03 (m, 2H).

LC/MS (m/z) [M+1]⁺ 571.2 (calculated for C₂₇H₂₂ClF₃N₆OS, 570.12).

Example 1601-(1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidin-4-yl)-3-ethyl-urea

1-(1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidin-4-yl)-3-ethyl-ureawas prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 1-Ethyl-3-piperidin-4-yl-urea following General Procedure B.

¹H NMR (400 MHz, DMSO) δ 8.35 (d, 1H), 8.15 (d, 1H), 8.11 (s, 1H),7.98-7.96 (m, 1H), 7.81-7.79 (m, 2H), 7.70 (dd, 1H), 6.91 (d, 1H), 5.98(s, 2H), 5.92 (d, 1H), 5.76 (t, 1H), 4.47-4.43 (m, 1H), 3.83-3.73 (m,2H), 3.59-3.52 (m, 1H), 3.49-3.42 (m, 1H), 3.04-2.97 (m, 2H), 1.99-1.98m, 2H), 1.46-1.39 (m, 2H), 0.98 (t, 3H).

LC/MS (m/z) [M+1]⁺ 625.1 (calculated for C₂₈H₂₆F₆N₆O₂S, 624.17).

Example 1615-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-methylamino-azepan-1-yl)-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-methylamino-azepan-1-yl)-thiazol-4-onewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-oneand Azepan-3-yl-methyl-amine following General Procedure B.

¹H NMR (400 MHz, CDCl₃) δ 8.20-8.17 (m, 1H), 7.98-7.89 (m, 2H), 7.71 (d,1H), 7.56-7.51 (m, 1H), 7.34-7.27 (m, 2H), 6.65 (dd, 1H), 5.78 (d, 1H),4.33-4.22 (m, 1H), 3.91-3.84 (m, 1H), 3.78-3.70 (m, 1H), 3.39 (dd,0.5H), 3.12 (br s, 1H), 2.93-2.90 (m. 0.5H), 2.57 (s, 3H), 2.45 (br s,1H), 2.04-1.92 (m, 3H), 1.68-1.48 (m, 2H).

LC/MS (m/z) [M+1]⁺ 548.2 (calculated for C₂₆H₂₅ClF₃N₅OS, 547.14).

Example 1625-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-pyrrolidin-1-yl-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-pyrrolidin-1-yl-thiazol-4-onewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-oneand pyrrolidine following General Procedure B.

¹H NMR (400 MHz, DMSO) δ 8.34 (d, 1H), 8.12 (m, 1H), 7.89 (d, 1H),7.78-7.76 (m, 2H), 7.69-7.64 (m, 2H), 6.75 (d, 1H), 5.86 (s, 2H), 3.72(t, 2H), 3.65 (t, 2H), 2.04-1.99 (m, 4H).

LC/MS (m/z) [M+1]⁺ 491.2 (calculated for C₂₃H₁₈ClF₃N₄OS, 490.08).

Example 1635-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-dimethylaminomethyl-4-hydroxy-piperidin-1-yl)-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-dimethylaminomethyl-4-hydroxy-piperidin-1-yl)-thiazol-4-onewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-oneand 4-Dimethylaminomethyl-piperidin-4-ol following General Procedure B.

¹H NMR (400 MHz, CD₃OD) δ 8.23 (d, 1H), 8.08 (s, 1H), 7.86 (s, 1H), 7.79(d, 1H), 7.64 (dd, 1H), 7.54 (d, 1H), 7.48 (dd, 1H), 6.68 (d, 1H), 5.84(s, 2H), 4.65-4.61 (m, 1H), 3.85-3.82 (m, 2H), 3.68-3.61 (m, 1H), 3.26(s, 2H), 3.0 (s, 6H), 1.96-1.78 (m, 4H).

LC/MS (m/z) [M+1]⁺ 578.2 (calculated for C₂₇H₂₇ClF₃N₅O₂S, 577.15).

Example 1645-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-hydroxy-4-imidazol-1-ylmethyl-piperidin-1-yl)-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-hydroxy-4-imidazol-1-ylmethyl-piperidin-1-yl)-thiazol-4-onewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-oneand 4-Imidazol-1-ylmethyl-piperidin-4-ol following General Procedure B.

¹H NMR (400 MHz, DMSO) δ 8.232 (d, 1H), 8.13 (s, 1H), 7.89 (d, 1H),7.78-7.75 (m, 2H), 7.70-7.65 (m, 2H), 7.55 (d, 1H), 7.11 (s, 1H), 6.88(s, 1H), 6.76 (d, 1H), 5.86 (s, 2H), 4.46-4.42 (m, 1H), 3.98 (s, 2H),3.74-3.62 (m, 2H), 3.52-3.46 (m, 1H), 1.70-1.59 (m, 2H), 1.50-1.47 (m,2H).

LC/MS (m/z) [M+1]⁺ 601.2 (calculated for C₂₈H₂₄ClF₃N₆O₂S, 600.13).

Example 1655-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-ethyl-3-hydroxy-piperidin-1-yl)-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-ethyl-3-hydroxy-piperidin-1-yl)-thiazol-4-onewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-oneand 3-Ethyl-piperidin-3-ol following General Procedure B.

¹H NMR (400 MHz, DMSO) δ 8.33 (d, 1H), 8.05 (s, 1H), 7.89 (d, 1H), 7.79(d, 1H), 7.72 (s, 1H), 7.66-7.61 (m, 2H), 6.73 (d, 1H), 5.86 (s, 2H),4.44 (t, 1H), 3.53 (br s, 2H), 3.40-3.35 (m, 2H), 1.45-1.42 (m, 6H),0.83 (t, 3H).

LC/MS (m/z) [M+1]⁺ 549.1 (calculated for C₂₆H₂₄ClF₃N₄O₂S, 548.13).

Example 1665-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-hydroxy-[1,4′]bipiperidinyl-1′-yl)-thiazol-4-one

5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-hydroxy-[1,4′]bipiperidinyl-1′-yl)-thiazol-4-onewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-oneand [1,4′]Bipiperidinyl-3-ol following General Procedure B.

¹H NMR (400 MHz, CD₃OD) δ 8.21 (s, 1H), 8.07 (s, 1H), 7.86 (s, 1H), 7.79(d, 1H), 7.62 (dd, 1H), 7.52 (d, 1H), 7.47 (dd, 1H), 6.68 (d, 1H), 5.83(s, 2H), 4.98-4.94 (m, 1H), 4.13-4.10 (m, 1H), 3.59-3.53 (m, 2H),3.45-3.42 (m, 2H), 3.33-3.13 (m, 4H), 2.36-2.20 (m, 3H), 1.99-1.70 (m,5H).

LC/MS (m/z) [M+1]⁺ 604.2 (calculated for C₂₉H₂₉ClF₃N₅O₂S, 603.17).

Example 1678-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-1,3,8-triaza-spiro[4.5]decan-4-one

8-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-1,3,8-triaza-spiro[4.5]decan-4-onewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-oneand 1,3,8-Triaza-spiro[4.5]decan-4-one following General Procedure B.

¹H NMR (400 MHz, CD₃OD) δ 8.23 (d, 1H), 8.09 (s, 1H), 7.87 (s, 1H), 7.79(d, 1H), 7.65 (dd, 1H), 7.54 (d, 1H), 7.47 (dd, 1H), 6.68 (d, 1H), 5.84(s, 2H), 4.61 (s, 2H), 4.40-4.35 (m, 1H), 4.14-4.04 (m, 2H), 3.89-3.82(m, 1H), 2.28-2.17 (m, 2H), 2.09-1.97 (m, 2H).

LC/MS (m/z) [M+1]⁺ 575.2 (calculated for C₂₆H₂₂ClF₃N₆O₂S, 574.12).

Example 1685-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[3-(2-hydroxy-ethyl)-4-methyl-piperazin-1-yl]-thiazol-4-one

5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[3-(2-hydroxy-ethyl)-4-methyl-piperazin-1-yl]-thiazol-4-onewas prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 2-(1-Methyl-piperazin-2-yl)-ethanol following General Procedure B.

¹H NMR (400 MHz, CDCl₃) δ 8.22-8.21 (m, 1H), 7.98 (br s, 2H), 7.93 (s,1H), 7.63 (d, 1H), 7.56-7.54 (m, 1H), 7.32 (d, 1H), 6.82 (d, 1H), 5.88(s, 2H), 4.57 (d, 1H), 3.91-3.71 (m, 3H), 3.63-3.51 (m, 2H), 3.10-2.96(m, 2H), 2.57 (br s, 1H), 2.45 (s, 3H), 1.94-1.84 (m, 2H).

LC/MS (m/z) [M+1]⁺ 598.3 (calculated for C₂₇H₂₅F₆N₅O₂S, 597.16).

Example 1695-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3,4-dihydro-1H-pyrrolo[1,2-a]pyrazin-2-yl)-thiazol-4-one

5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3,4-dihydro-1H-pyrrolo[1,2-a]pyrazin-2-yl)-thiazol-4-onewas prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 1,2,3,4-Tetrahydro-pyrrolo[1,2-a]pyrazine following GeneralProcedure B.

¹H NMR (400 MHz, DMSO) δ 8.37 (dd, 1H), 8.19-8.17 (m, 1H), 8.12 (s, 1H),7.97 (d, 1H), 7.84-7.81 (m, 2H), 7.74-7.71 (m, 1H), 6.92 (dd, 1H), 6.79(t, 1H), 6.07-6.04 (m, 1H), 5.99-5.96 (m, 3H), 5.06 (s, 1H), 4.94 (s,1H), 4.28-4.25 (m, 1H), 4.23-4.21 (m, 1H), 4.17-4.15 (m, 1H), 4.07-4.04(m, 1H).

LC/MS (m/z) [M+1]⁺ 576.3 (calculated for C₂₇H₁₉F₆N₅OS, 575.12).

Example 1704-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-1,3-dimethyl-piperazin-2-one

4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-1,3-dimethyl-piperazin-2-onewas prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 1,3-Dimethyl-piperazin-2-one following General Procedure B.

¹H NMR (400 MHz, CDCl₃) δ 8.24-8.22 (m, 1H), 7.99-7.97 (m, 3H), 7.63 (d,1H), 7.55 (dd, 1H), 7.34 (d, 1H), 6.82 (d, 1H), 5.89 (s, 2H), 5.02-4.98(m, 1H), 4.45 (q, 1H), 3.88-3.86 (m, 1H), 3.73-3.60 (m, 3H), 3.43-3.39(m, 1H), 3.35-3.32 (m, 1H), 1.69 (d, 3H).

LC/MS (m/z) [M+1]⁺ 582.3 (calculated for C₂₆H₂₁F₆N₅O₂S, 581.13).

Example 1715-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2-dimethylaminomethyl-morpholin-4-yl)-thiazol-4-one

5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2-dimethylaminomethyl-morpholin-4-yl)-thiazol-4-onewas prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand Dimethyl-morpholin-2-ylmethyl-amine following General Procedure B.

¹H NMR (400 MHz, CDCl₃) δ 8.22 (dd, 1H), 7.99-7.98 (m, 2H), 7.95 (s,1H), 7.62 (d, 1H), 7.55 (ddd, 1H), 7.32 (dd, 1H), 6.82 (d, 1H), 5.88 (s,2H), 4.86-4.75 (m, 1H), 4.14-4.04 (m, 1H), 3.79-3.57 (m, 3H), 3.41-3.35(m, 0.5H), 3.29-3.23 (m, 0.5H), 3.07-3.01 (m, 0.5H), 2.59-2.51 (m, 1H),2.41 (dd, 0.5H), 2.31 (s, 3H), 2.28 (s, 3H), 2.28-2.23 (m, 1H).

LC/MS (m/z) [M+1]⁺ 598.3 (calculated for C₂₇H₂₅F₆N₅O₂S, 597.16).

Example 1725-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2(R)-(2-hydroxymethyl-morpholin-4-yl)-thiazol-4-one

A. 2-(2-Hydroxymethyl-morpholin-4-A-thiazol-4-one was prepared from2-Methylsulfanyl-thiazol-4-one and Morpholin-2-yl-methanol followinggeneral procedure D.

¹H NMR (400 MHz, CDCl₃) δ 4.72-4.66 (m, 1H), 4.11-4.00 (m, 1H), 3.97 (s,2H), 3.80-3.56 (m, 4H), 3.51-3.26 (m, 2H), 3.19 (dd, 1H), 1.96-1.91 (m,1H).

LC/MS (m/z) [M+1]⁺ 217.2 (calculated for C₈H₁₂N₂O₃S, 216.06).

B.5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2(R)-(2-hydroxymethyl-morpholin-4-yl)-thiazol-4-onewas prepared from1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and2(R)-(2-Hydroxymethyl-morpholin-4-yl)-thiazol-4-one following GeneralProcedure D.

¹H NMR (400 MHz, CDCl₃) δ 8.22-8.21 (m, 1H), 7.98 (br s, 2H), 7.95 (s,1H), 7.62 (d, 1H), 7.56-7.53 (m, 1H), 7.32 (d, 1H), 6.83 (d, 1H), 5.88(s, 2H), 4.84-4.78 (m, 1H), 4.16-4.06 (m, 1H), 3.84-3.49 (6H), 3.41-3.25(m, 1H), 1.99-1.93 (m, 1H).

LC/MS (m/z) [M+1]⁺ 571.2 (calculated for C₂₅H₂₀F₆N₄O₃S, 570.12).

Example 173 Pyrrolidine-1-sulfonic acid(1-{5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carbonyl)-amide

A. 1-(4-Oxo-4,5-dihydro-thiazol-2-yl)-piperidine-4-carboxylic acid

To a solution of 2-methylsulfanyl-thiazol-4-one (4.4 g, 30 mmol) in MeOH(60 mL) was added piperidine-4-carboxylic acid (3.9 g, 30 mmol). Themixture was stirred at room temperature for 16 hours. The resultingsolid was collected by filtration, washed with fresh MeOH and dried togive the title compound.

¹H NMR (400 MHz, DMSO): 12.43 (s, 1H), 4.36 (m, 1H), 3.99 (s, 2H), 3.66(m, 1H), 3.34 (m, 2H), 2.61 (m, 1H), 1.94 (m, 2H), 1.56 (m, 2H).

LC/MS (m/z) [M+1]⁺ 229.1 (calculated for C₉H₁₂N₂O₃S, 228.1).

B. Pyrrolidine-1-sulfonic acid[1-(4-oxo-4,5-dihydro-thiazol-2-A-piperidine-4-carbonyl]-amide

A solution of 1-(4-Oxo-4,5-dihydro-thiazol-2-yl)piperidine-4-carboxylicacid (0.075 g, 0.33 mmol) and carbonyl diimidazole (0.107 g, 0.65 mmol)in THF (3 mL) was heated under stirring at 45 to 50° C. for 3 hours. Itwas then added to the homogenous reaction mixture a solution ofPyrrolidine-1-sulfonic acid amide (0.099 g, 0.65 mmol) in THF (1 mL)containing Diazabicyclo [5.4.0]undec-7-ene (0.15 g, 0.98 mmol). Theresulting reaction mixture was stirred at 45-50° C. for 30 minutes thenat room temperature for 12 hours, diluted with dichloromethane andquenched with 10% aqueous HCl. The dichloromethane layer was thensuccessively washed with water, brine, dried over Na₂SO₄, filtered, andthe solvent evaporated in vacuo to yield the title compound as a gum (64mg, 54%).

¹H NMR (400 MHz, CDCl₃) δ 3.99 (s, 3H), 3.53-3.42 (m, 4H), 3.37-3.30 (m,4H), 2.72-2.66 (m, 1H), 1.96-1.81 (m, 8H).

LC/MS (m/z) [M+1]⁺ 361.2 (calculated for C₁₃H₂₀N₄O₄S₂, 360.09).

C. Pyrrolidine-1-sulfonic acid(1-{5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carbonyl)-amidewas prepared from1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde andPyrrolidine-1-sulfonic acid[1-(4-oxo-4,5-dihydro-thiazol-2-yl)-piperidine-4-carbonyl]-amidefollowing General Procedure E.

¹H NMR (400 MHz, CDCl₃) δ 9.31 (br s, 1H), 8.19 (d, 1H), 7.98-7.96 (m,2H), 7.93 (s, 1H), 7.62 (d, 1H), 7.53 (dd, 1H), 7.28 (d, 1H), 6.81 (d,1H), 5.86 (s, 2H), 4.78-4.75 (m, 1H), 3.95-3.92 (m, 1H), 3.55-3.39 (m,6H), 2.79-2.74 (m, 1H), 2.11-2.08 (m, 2H), 2.04-1.90 (m, 8H).

LC/MS (m/z) [M+1]⁺ 715.3 (calculated for C₃₀H₂₈F₆N₆O₄S₂, 714.15).

Example 174 Pyrrolidine-1-sulfonic acid(1-{5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carbonyl)-amide

A. 1-(4-Oxo-4,5-dihydro-thiazol-2-yl)-piperidine-4-carboxylic acid

To a solution of 2-methylsulfanyl-thiazol-4-one (4.4 g, 30 mmol) in MeOH(60 mL) was added piperidine-4-carboxylic acid (3.9 g, 30 mmol). Themixture was stirred at room temperature for 16 hours. The resultingsolid was collected by filtration and washed with fresh MeOH.

¹H NMR (400 MHz, DMSO): 12.43 (s, 1H), 4.36 (m, 1H), 3.99 (s, 2H), 3.66(m, 1H), 3.34 (m, 2H), 2.61 (m, 1H), 1.94 (m, 2H), 1.56 (m, 2H).

LC/MS (m/z) [M+1]⁺ 229.1 (calculated for C₉H₁₂N₂O₃S, 228.1).

B. Pyrrolidine-1-sulfonic acid[1-(4-oxo-4,5-dihydro-thiazol-2-A-piperidine-4-carbonyl]-amide

A solution of 1-(4-Oxo-4,5-dihydro-thiazol-2-yl)-piperidine-4-carboxylicacid (0.075 g, 0.33 mmol) and carbonyl diimidazole (0.107 g, 0.65 mmol)in THF (3 mL) was heated under stirring at 45 to 50° C. for 3 hours. Itwas then added to the homogenous reaction mixture a solution ofPyrrolidine-1-sulfonic acid amide (0.099 g, 0.65 mmol) in THF (1 mL)containing Diazabicyclo [5.4.0]undec-7-ene (0.15 g, 0.98 mmol). Theresulting reaction mixture was stirred at 45-50° C. for 30 minutes thenat room temperature for 12 hours, diluted with dichloromethane andquenched with 10% aqueous HCl. The dichloromethane layer was thensuccessively washed with water, brine, dried over Na₂SO₄, filtered, andthe solvent evaporated in vacuo to yield the title compound as a gum (64mg, 54%).

¹H NMR (400 MHz, CDCl₃) δ 3.99 (s, 3H), 3.53-3.42 (m, 4H), 3.37-3.30 (m,4H), 2.72-2.66 (m, 1H), 1.96-1.81 (m, 8H).

LC/MS (m/z) [M+1]⁺ 361.2 (calculated for C₁₃H₂₀N₄O₄S₂, 360.09).

C. Pyrrolidine-1-sulfonic acid(1-{5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carbonyl)-amidewas prepared from1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde andPyrrolidine-1-sulfonic acid[1-(4-oxo-4,5-dihydro-thiazol-2-yl)-piperidine-4-carbonyl]-amidefollowing General Procedure E.

¹H NMR (400 MHz, CDCl₃) δ 8.16 (d, 1H), 7.94-7.92 (m, 2H), 7.70 (d, 1H),7.50 (dd, 1H), 7.33 (dd, 1H), 7.27-7.25 (m, 1H), 6.65 (d, 1H), 5.75 (s,2H), 4.77-4.74 (m, 1H), 3.94-3.91 (m, 1H), 3.54-3.38 (m, 6H), 2.84-2.77(m, 1H), 2.11-2.08 (m, 2H), 2.04-1.86 (m, 8H).

LC/MS (m/z) [M+1]⁺ 715.3 (calculated for C₃₀H₂₈F₆N₆O₄S₂, 714.15).

Example 1755-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-iodo-1H-indazol-5-ylmethylene]-2(S)-(2-hydroxymethyl-morpholin-4-yl)-thiazol-4-one

A. 2-(2-Hydroxymethyl-morpholin-4-yl)-thiazol-4-one was prepared from2-Methylsulfanyl-thiazol-4-one and Morpholin-2-yl-methanol followinggeneral procedure E.

¹H NMR (400 MHz, CDCl₃) δ 4.72-4.66 (m, 1H), 4.11-4.00 (m, 1H), 3.97 (s,2H), 3.80-3.56 (m, 4H), 3.51-3.26 (m, 2H), 3.19 (dd, 1H), 1.96-1.91 (m,1H).

LC/MS (m/z) [M+1]⁺ 217.2 (calculated for C₈H₁₂N₂O₃S, 216.06).

B. 1-(2,4-Bis-trifluoromethyl-benzyl)-3-iodo-1H-indazole-5-carbaldehydewas prepared from 3-Iodo-1H-indazole-5-carbaldehyde and1-Bromomethyl-2,4-bis-trifluoromethyl-benzene following generalprocedure A.

¹H NMR (400 MHz, CDCl₃) δ 10.10 (s, 1H), 8.09 (dd, 1H), 8.01-7.99 (m,2H), 7.66 (d, 1H), 7.34 (d, 1H), 6.91 (d, 1H), 5.91 (s, 2H).

LC/MS (m/z) [M+1]⁺ 497.9 (calculated for C₁₇H₉F₆₁N₂O, 497.97).

C.5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-iodo-1H-indazol-5-ylmethylene]-2(S)-(2-hydroxymethyl-morpholin-4-yl)-thiazol-4-onewas prepared from1-(2,4-Bis-trifluoromethyl-benzyl)-3-iodo-1H-indazole-5-carbaldehyde and2-(2-Hydroxymethyl-morpholin-4-yl)-thiazol-4-one following GeneralProcedure E.

¹H NMR (400 MHz, CDCl₃) δ 7.98-7.95 (m, 2H), 7.69 (s, 1H), 7.65 (d, 1H),7.61-7.57 (m, 1H), 7.28 (d, 1H), 6.90 (d, 1H), 5.88 (s, 2H), 4.85-4.78(m, 1H), 4.17-4.07 (m, 1H), 3.84-3.49 (m, 6H), 3.42-3.26 (m, 1H).

LC/MS (m/z) [M+1]⁺ 697.0 (calculated for C₂₅H₁₉F₆₁N₄O₃S, 696.01).

Example 1761-{5-[1-(4-Fluoro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carboxylicacid

A. 1-(4-Fluoro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde wasprepared from 1H-Indazole-5-carbaldehyde and1-Bromomethyl-4-fluoro-2-trifluoromethyl-benzene following GeneralProcedure A.

¹H NMR (400 MHz, CDCl₃): δ 10.09 (s, 1H), 8.34 (s, 1H), 8.30 (s, 1H),7.96 (dd, 1H), 7.47 (dd, 1H), 7.40 (d, 1H), 6.77 (dd, 1H), 5.86 (s, 2H).

LC/MS (m/z) [M+1]⁺ 323.3 (calculated for C₁₆H₁₀F₄N₂O, 322.2).

B.1-{5-[1-(4-Fluoro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carboxylicacid was prepared from1-(4-Fluoro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and1-(4-Oxo-4,5-dihydro-thiazol-2-yl)piperidine-4-carboxylic acid followingGeneral Procedure E.

¹H NMR (400 MHz, DMSO): δ 12.4 (br s, 1H), 8.31 (d, 1H), 8.13 (s, 1H),7.78-7.76 (m, 2H), 7.73 (dd, 1H), 7.69 (dd, 1H), 7.45 (td, 1H), 6.85(dd, 1H), 5.85 (s, 2H), 4.48-4.45 (m, 1H), 3.85-3.81 (m, 1H), 3.58-3.51(m, 1H), 3.48-3.41 (m, 1H), 2.72-2.66 (m, 1H), 2.09-1.98 (m, 2H),1.7-1.61 (m, 2H). LC/MS (m/z) [M+1]⁺ 533.2 (calculated forC₂₅H₂₀F₄N₄O₃S, 532.12).

Example 1775-[1-(4-Fluoro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-((2S)-2-hydroxymethyl-morpholin-4-yl)-thiazol-4-one

5-[1-(4-Fluoro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-((2S)-2-hydroxymethyl-morpholin-4-yl)-thiazol-4-onewas prepared from5-[1-(4-Fluoro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-oneand (2S) Morpholin-2-yl-methanol following General Procedure B.

¹H NMR (400 MHz, CDCl₃): δ 8.19 (dd, 1H), 7.97-7.95 (m, 2H), 7.54-7.52(m, 1H), 7.44 (dd, 1H), 7.32 (d, 1H), 7.07 (td, 1H), 6.74 (dd, 1H), 5.78(s, 2H), 4.84-4.78 (m, 1H), 4.16-4.06 (m, 1H), 3.84-3.49 (m, 6H),3.41-3.25 (m, 1H), 2.06-1.99 (m, 1H). LC/MS (m/z) [M+1]⁺ 521.2(calculated for C₂₄H₂₀F₄N₄O₃S, 520.12).

Example 1785-[1-(4-Fluoro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-((3R)-3-hydroxymethyl-piperazin-1-yl)-thiazol-4-one

A.4-{5-[1-(4-Fluoro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester was prepared from1-(4-Fluoro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and2(R)—Hydroxymethyl-4-(4-oxo-4,5-dihydro-thiazol-2-yl)piperazine-1-carboxylicacid tert-butyl ester following general procedure D.

¹H NMR (400 MHz, CDCl₃): δ 8.16-8.13 (m, 1H), 7.91-7.86 (m, 2H),7.49-7.43 (m, 2H), 7.29-7.23 (m, 1H), 7.09-7.43 (m, 1H), 6.77-6.71 (m,1H), 5.77-5.74 (m, 2H), 4.92-4.88 (m, 0.5H), 4.76-4.72 (m, 0.5H), 4.38(br s, 1H), 4.18-4.13 (m. 0.5H), 4.07-4.02 (m, 1H), 3.81-3.51 (m, 3.5H),3.45-3.32 (m, 1H), 3.23-3.17 (m, 1H), 1.49 (d, 9H).

LC/MS (m/z) [M+1]⁺ 619.9 (calculated for C₂₉H₂₉F₄N₅O₄S, 619.19).

B.5-[1-(4-Fluoro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-((3R)-3-hydroxymethyl-piperazin-1-yl)-thiazol-4-onewas prepared from4-{5-[1-(4-Fluoro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester following general procedure H.

¹H NMR (400 MHz, CDCl₃): δ 8.19 (d, 1H), 7.97-7.93 (m, 2H), 7.54 (d,1H), 7.44 (dd, 1H), 7.32 (d, 1H), 7.07 (td, 1H), 6.74 (dd, 1H), 5.79 (s,2H), 4.79-4.74 (m, 1H), 3.77-3.73 (m, 2H), 3.69-3.65 (m, 0.5H),3.60-3.56 (m, 0.5H), 3.52-3.45 (m, 0.5H), 3.36-3.29 (m, 1H), 3.25-3.15(m, 1.5H), 3.04-2.94 (m, 2H).

LC/MS (m/z) [M+1]⁺ 520.1 (calculated for C₂₄H₂₁F₄N₅O₂S, 519.14).

Example 1795-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4,7-diaza-spiro[2.5]oct-7-yl)-thiazol-4-one

A.7-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-4,7-diaza-spiro[2.5]octane-4-carboxylicacid tert-butyl ester was prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-oneand 4,7-Diaza-spiro[2.5]octane-4-carboxylic acid tert-butyl esterfollowing general procedure B.

¹H NMR (400 MHz, CDCl₃): δ 8.22 (s, 1H), 7.99-7.94 (m, 3H), 7.63-7.61(m, 1H), 7.57-7.52 (m, 1H), 7.33-7.30 (m, 1H), 6.82 (d, 1H), 5.88 (s,2H), 4.11-4.09 (m, 1H), 3.93 (s, 1H), 3.74-3.72 (m, 1H), 3.68-3.63 (m,2H), 3.45 (s, 1H), 1.5 (s, 9H), 1.21-1.10 (m, 1H), 1.05-1.02 (m, 1H),0.95 (br s, 2H).

LC/MS (m/z) [M+1]⁺ 666.9 (calculated for C₃₁H₂₉F₆N₅O₃S, 665.19).

B.5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4,7-diaza-spiro[2.5]oct-7-yl)-thiazol-4-onewas prepared from7-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-4,7-diaza-spiro[2.5]octane-4-carboxylicacid tert-butyl ester following general procedure H.

¹H NMR (400 MHz, CDCl₃): δ 8.21 (d, 1H), 7.98-7.96 (m, 2H), 7.93 (s,1H), 7.62 (d, 1H), 7.55 (td, 1H), 7.31 (dd, 1H), 6.81 (d, 1H), 5.88 (s,2H), 4.09-4.06 (m, 1H), 3.94 (s, 1H), 3.64-3.62 (m, 1H), 3.47 (s, 1H),3.15-3.12 (m, 1H), 3.09-3.07 (m, 1H), 0.75-0.65 (m, 4H).

LC/MS (m/z) [M+1]⁺ 566.1 (calculated for C₂₆H₂₁F₆N₅OS, 565.14).

Example 1805-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-methyl-1H-indazol-5-ylmethylene]-2-(2-(S)-hydroxymethyl-morpholin-4-yl)-thiazol-4-one

A. 3-Methyl-1H-indazole-5-carbaldehyde

To an Argon flushed flask of anhydrous THF (81 mL) cooled to −78° C. wasadded a 1.7M solution of tert-butyllithium in n-pentane (27 mL, 45.6mmol). After stirring the solution at −78° C. for 15 minutes, a solutionof 5-Bromo-3-methyl-1H-indazole (3 g, 14.2 mmol) in THF (42 mL) wasadded dropwise such that the temperature of the solution did not exceed−70° C. After stirring the solution at −78° C. for 30 minutes, anhydrousDMF (3.15 g, 43.09 mmol) was added dropwise. The reaction mixture wasthen stirred at −78° C. for 30 minutes, warmed to room temperature andstirred for 1.5 hours. The reaction mixture was cooled down to 0° C. andit was added carefully water (36 mL) and ethyl acetate. The ethylacetate layer was washed with brine, dried over Na₂SO₄, filtered, andthe solvent evaporated in vacuo. The residue was purified by flashcolumn chromatography on silica gel (heptane/EtOAc 6:4 v/v) to affordwhite solid (1.6 g, 70%).

¹H NMR (400 MHz, CDCl₃) δ10.09 (br s, 1H), 10.07 (s, 1H), 8.24 (s, 1H),7.95 (dd, 1H), 7.52 (d, 1H), 2.66 (s, 3H).

LC/MS (m/z) [M+1]⁺ 161.1 (calculated for C₉H₈N₂O, 160.06).

(compound described: WO 2008071451)

B.1-(2,4-Bis-trifluoromethyl-benzyl)-3-methyl-1H-indazole-5-carbaldehydewas prepared from 3-Methyl-1H-indazole-5-carbaldehyde and1-Bromomethyl-2,4-bis-trifluoromethyl-benzene following generalprocedure A.

¹H NMR (400 MHz, CDCl₃) δ 10.03 (s, 1H), 8.19 (d, 1H), 7.99 (s, 1H),7.86 (dd, 1H), 7.74 (d, 1H), 6.68 (d, 1H), 5.88 (s, 2H), 2.61 (s, 3H).

LC/MS (m/z) [M+1]⁺ 387.1 (calculated for C₁₈H₁₂F₈N₂O, 386.09).

C.5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-methyl-1H-indazol-5-ylmethylene]-2-(2-(S)-hydroxymethyl-morpholin-4-yl)-thiazol-4-onewas prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-methyl-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-oneand 2-(S)-Morpholin-2-yl-methanol following general procedure B.

¹H NMR (400 MHz, CDCl₃): δ 7.97 (s, 2H), 7.88 (s, 1H), 7.61 (d, 1H),7.55-7.52 (m, 1H), 7.25 (d, 1H), 6.81 (d, 1H), 5.80 (s, 2H), 4.84-4.78(m, 1H), 4.16-4.06 (m, 1H), 3.82-3.49 (m, 6H), 3.41-3.25 (m, 1H), 2.67(d, 3H), 1.92-1.86 (m, 1H).

LC/MS (m/z) [M+1]⁺ 585.2 (calculated for C₂₆H₂₂F₆N₄O₃S, 584.13).

Example 1815-[1-(4-Chloro-2-trifluoromethyl-benzyl)-3-methyl-1H-indazol-5-ylmethylene]-2-(2-(S)-hydroxymethyl-morpholin-4-yl)-thiazol-4-one

A.1-(4-Chloro-2-trifluoromethyl-benzyl)-3-methyl-1H-indazole-5-carbaldehydewas prepared from 3-Methyl-1H-indazole-5-carbaldehyde and1-Bromomethyl-4-chloro-2-trifluoromethyl-benzene following generalprocedure A.

¹H NMR (400 MHz, CDCl₃) δ 10.06 (s, 1H), 8.25 (d, 1H), 7.91 (dd, 1H),7.71 (d, 1H), 7.33 (dd, 1H), 7.29 (d, 1H), 6.65 (d, 1H), 5.74 (s, 2H),2.68 (s, 3H).

LC/MS (m/z) [M+1]⁺ 353.0 (calculated for C₁₇H₁₂ClF₃N₂O, 352.06).

B.5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-3-methyl-1H-indazol-5-ylmethylene]-2-(2-(S)-hydroxymethyl-morpholin-4-yl)-thiazol-4-onewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-3-methyl-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-oneand 2-(S)-Morpholin-2-yl-methanol following general procedure B.

¹H NMR (400 MHz, CDCl₃): δ 7.96 (s, 1H), 7.85 (s, 1H), 7.69 (d, 1H),7.53-7.50 (m, 1H), 7.32 (dd, 1H), 7.23 (d, 1H), 6.64 (d, 1H), 5.71 (s,2H), 4.84-4.77 (m, 1H), 4.16-4.06 (m, 1H), 3.88-3.48 (m, 6H), 3.41-3.24(m, 1H), 2.65 (d, 3H), 2.10-2.04 (m, 1H).

LC/MS (m/z) [M+1]⁺ 551.2 (calculated for C₂₅H₂₂ClF₃N₄O₃S, 550.11).

Example 1825-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-methyl-1H-indazol-5-ylmethylene]-2-(3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one

A.4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-methyl-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester was prepared from1-(2,4-Bis-trifluoromethyl-benzyl)-3-methyl-1H-indazole-5-carbaldehydeand2-(R)—Hydroxymethyl-4-(4-oxo-4,5-dihydro-thiazol-2-yl)-piperazine-1-carboxylicacid tert-butyl ester following general procedure D.

¹H NMR (400 MHz, CDCl₃): δ 7.96-7.94 (m, 2H), 7.86-7.84 (m, 1H),7.62-7.60 (m, 1H), 7.52-7.50 (m, 1H), 7.25-7.22 (m, 1H), 6.83-6.79 (m,1H), 5.81-5.79 (m, 2H), 4.93-4.88 (m, 0.5H), 4.79-4.74 (m, 0.5H), 4.37(br s, 1H), 4.19-4.15 (m. 0.5H), 4.04-3.99 (m, 1H), 3.82-3.51 (m, 3.5H),3.46-3.32 (m, 1H), 3.22-3.16 (m, 1H), 2.66 (d, 3H), 1.49 (d, 9H).

LC/MS (m/z) [M+1]⁺ 683.9 (calculated for C₃₁H₃₁F₆N₅O₄S, 683.20).

B.5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-methyl-1H-indazol-5-ylmethylene]-2-(3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-onewas prepared from4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-methyl-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester following general procedure H.

¹H NMR (400 MHz, CDCl₃): δ 7.97-7.94 (m, 2H), 7.87 (s, 1H), 7.61 (d,1H), 7.55-7.52 (m, 1H), 7.24 (d, 1H), 6.80 (d, 1H), 5.80 (s, 2H),4.79-4.74 (m, 1H), 3.77-3.74 (m, 2H), 3.69-3.65 (m, 0.5H), 3.61-3.56 (m,0.5H), 3.53-3.45 (m, 0.5H), 3.37-3.29 (m, 1H), 3.27-3.16 (m, 1.5H),3.04-2.97 (m, 2H), 2.67 (s, 3H).

LC/MS (m/z) [M+1]⁺ 584.2 (calculated for C₂₆H₂₃F₆N₅O₂S, 583.15).

Example 1835-[1-(4-Chloro-2-trifluoromethyl-benzyl)-3-methyl-1H-indazol-5-ylmethylene]-2-(3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one

A.4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-3-methyl-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester was prepared from1-(4-Chloro-2-trifluoromethyl-benzyl)-3-methyl-1H-indazole-5-carbaldehydeand2-(R)—Hydroxymethyl-4-(4-oxo-4,5-dihydro-thiazol-2-yl)-piperazine-1-carboxylicacid tert-butyl ester following general procedure D.

¹H NMR (400 MHz, CDCl₃): δ 7.95-7.93 (m, 1H), 7.84-7.82 (m, 1H), 7.69(s, 1H), 7.51-7.48 (m, 1H), 7.33-7.30 (m, 1H), 7.23-7.19 (m, 1H),6.66-6.62 (m, 1H), 5.71-5.69 (m, 2H), 4.93-4.88 (m, 0.5H), 4.78-4.74 (m,0.5H), 4.38 (br s, 1H), 4.18-4.12 (m. 0.5H), 4.04-3.99 (m, 1H),3.82-3.70 (m, 1.5H), 3.64-3.31 (m, 3H), 3.22-3.15 (m, 1H), 2.65 (d, 3H),1.49 (d, 9H).

LC/MS (m/z) [M+1]⁺ 650.0 (calculated for C₃₀H₃₁ClF₃N₅O₄S, 649.17).

B.5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-3-methyl-1H-indazol-5-ylmethylene]-2-(3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-onewas prepared from4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-3-methyl-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester following general procedure H.

¹H NMR (400 MHz, CDCl₃): δ 7.94 (s, 1H), 7.86 (s, 1H), 7.69 (d, 1H),7.54-7.51 (m, 1H), 7.32 (dd, 1H), 7.23 (d, 1H), 6.64 (d, 1H), 5.71 (s,2H), 4.79-4.74 (m, 1H), 3.77-3.73 (m, 2H), 3.69-3.65 (m, 0.5H),3.60-3.56 (m, 0.5H), 3.52-3.45 (m, 0.5H), 3.37-3.29 (m, 1H), 3.27-3.15(m, 1.5H), 3.04-2.93 (m, 2H), 2.66 (s, 3H).

LC/MS (m/z) [M+1]⁺ 550.2 (calculated for C₂₅H₂₃ClF₃N₅O₂S, 549.12).

Example 1845-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-chloro-1H-indazol-5-ylmethylene]-2-(2-(S)-hydroxymethyl-morpholin-4-yl)-thiazol-4-one

A. 3-Chloro-1H-indazole-5-carbaldehyde

To a solution of 1H-Indazole-5-carbaldehyde (3.2 g, 21.89 mmol) inacetonitrile (140 mL) was added N-Chlorosuccinimide (3.5 g, 26.27 mmol).After stirring for 50 hours at 65 to 70° C., the precipitate wasfiltered, washed with cold acetonitrile, abundantly with water and driedto afford the title compound as a white solid (2.15 g, 54%).

¹H NMR (400 MHz, CDCl₃) δ13.78 (s, 1H), 10.08 (s, 1H), 8.37 (d, 1H),7.92 (dd, 1H), 7.72 (d, 1H).

LC/MS (m/z) [M+1]⁺ 181.2 (calculated for C₈H₅ClN₂O, 180.01).

B.1-(2,4-Bis-trifluoromethyl-benzyl)-3-chloro-1H-indazole-5-carbaldehydewas prepared from 3-Chloro-1H-indazole-5-carbaldehyde and1-Bromomethyl-2,4-bis-trifluoromethyl-benzene following generalprocedure A.

¹H NMR (400 MHz, CDCl₃) δ 10.09 (s, 1H), 8.28 (s, 1H), 8.01-7.99 (m,2H), 7.68 (d, 1H), 7.36 (d, 1H), 6.98 (d, 1H), 5.83 (s, 2H).

LC/MS (m/z) [M+1]⁺ 405.9 (calculated for C₁₇H₉ClF₆N₂O, 406.03).

C.5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-chloro-1H-indazol-5-ylmethylene]-2-(2-(S)-hydroxymethyl-morpholin-4-yl)-thiazol-4-onewas prepared from1-(2,4-Bis-trifluoromethyl-benzyl)-3-chloro-1H-indazole-5-carbaldehydeand 2-(2-(S)—Hydroxymethyl-morpholin-4-yl)-thiazol-4-one followinggeneral procedure D.

¹H NMR (400 MHz, CDCl₃): δ 7.98 (s, 1H), 7.94 (s, 1H), 7.89 (s, 1H),7.67 (d, 1H), 7.60-7.57 (m, 1H), 7.31 (d, 1H), 6.97 (d, 1H), 5.81 (s,2H), 4.84-4.79 (m, 1H), 4.17-4.07 (m, 1H), 3.85-3.48 (m, 6H), 3.41-3.26(m, 1H), 1.91-1.85 (m, 1H).

LC/MS (m/z) [M+1]⁺ 605.2 (calculated for C₂₅H₁₉ClF₆N₄O₃S, 604.08).

Example 1855-[3-Chloro-1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2-(S)-hydroxymethyl-morpholin-4-yl)-thiazol-4-one

A.3-Chloro-1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehydewas prepared from 3-Chloro-1H-indazole-5-carbaldehyde and1-Bromomethyl-4-chloro-2-trifluoromethyl-benzene following generalprocedure A.

¹H NMR (400 MHz, CDCl₃) δ 10.09 (s, 1H), 8.29-8.28 (dd, 1H), 8.01-7.99(m, 2H), 7.68 (d, 1H), 7.36 (d, 1H), 6.98 (d, 1H), 5.84 (s, 2H).

LC/MS (m/z) [M+1]⁺ 372.0 (calculated for C₁₆H₉Cl₂F₃N₂O, 372.0).

B.5-[3-Chloro-1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2-hydroxymethyl-morpholin-4-yl)-thiazol-4-onewas prepared from3-Chloro-1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehydeand 2-(2-(S)—Hydroxymethyl-morpholin-4-yl)-thiazol-4-one followinggeneral procedure D.

¹H NMR (400 MHz, CDCl₃): δ 7.92 (s, 1H), 7.86 (s, 1H), 7.89 (s, 1H),7.71 (d, 1H), 7.58-7.55 (m, 1H), 7.38 (dd, 1H), 7.29 (d, 1H), 6.81 (d,1H), 5.72 (s, 2H), 4.84-4.78 (m, 1H), 4.17-4.07 (m, 1H), 3.85-3.48 (m,6H), 3.42-3.26 (m, 1H), 2.06-1.99 (m, 1H).

LC/MS (m/z) [M+1]⁺ 571.3 (calculated for C₂₄H₁₉Cl₂F₃N₄O₃S, 570.05).

Example 1865-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-chloro-1H-indazol-5-ylmethylene]-2-(3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one

A.4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-chloro-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester was prepared from1-(2,4-Bis-trifluoromethyl-benzyl)-3-chloro-1H-indazole-5-carbaldehydeand2-(R)—Hydroxymethyl-4-(4-oxo-4,5-dihydro-thiazol-2-yl)-piperazine-1-carboxylicacid tert-butyl ester following general procedure D.

¹H NMR (400 MHz, CDCl₃): δ 7.98 (s, 1H), 7.89-7.87 (m, 1H), 7.83-7.80(m, 1H), 7.68-7.66 (m, 1H), 7.54 (dd, 1H), 7.29-7.25 (m, 1H), 6.98-6.94(m, 1H), 5.80-5.78 (m, 2H), 4.93-4.89 (m, 0.5H), 4.76-4.73 (m, 0.5H),4.37 (br s, 1H), 4.19-4.14 (m. 0.5H), 4.06-4.00 (m, 1H), 3.84-3.52 (m,3.5H), 3.46-3.33 (m, 1H), 3.23-3.21 (m, 1H), 1.49 (d, 9H).

LC/MS (m/z) [M+1]⁺ 704.0 (calculated for C₃₀H₂₈ClF₆N₅O₄S, 703.15).

B.5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-chloro-1H-indazol-5-ylmethylene]-2-(3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-onewas prepared from4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-chloro-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester following general procedure H.

¹H NMR (400 MHz, CDCl₃): δ 7.98 (s, 1H), 7.90-7.87 (m, 2H), 7.67 (d,1H), 7.59-7.56 (m, 1H), 7.30 (d, 1H), 6.96 (d, 1H), 5.80 (s, 2H),4.79-4.74 (m, 1H), 3.78-3.73 (m, 2H), 3.70-3.66 (m, 0.5H), 3.61-3.57 (m,0.5H), 3.54-3.47 (m, 0.5H), 3.38-3.30 (m, 1H), 3.28-3.16 (m, 1.5H),3.05-2.93 (m, 2H).

LC/MS (m/z) [M+1]⁺ 604.2 (calculated for C₂₅H₂₀ClF₆N₅O₂S, 603.09).

Example 1875-[3-Chloro-1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one

A.4-{5-[3-Chloro-1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester was prepared from3-Chloro-1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehydeand2-(R)—Hydroxymethyl-4-(4-oxo-4,5-dihydro-thiazol-2-yl)-piperazine-1-carboxylicacid tert-butyl ester following general procedure D.

¹H NMR (400 MHz, CDCl₃): δ 7.92-7.89 (m, 1H), 7.84-7.81 (m, 1H), 7.71(s, 1H), 7.56-7.53 (m, 1H), 7.39-7.36 (m, 1H), 7.29-7.27 (m, 1H),6.82-6.78 (m, 1H), 5.71-5.70 (m, 2H), 4.93-4.89 (m, 0.5H), 4.78-4.74 (m,0.5H), 4.39 (br s, 1H), 4.20-4.15 (m. 0.5H), 4.05-4.0 (m, 1H), 3.84-3.72(m, 1.5H), 3.65-3.32 (m, 3H), 3.23-3.17 (m, 1H), 1.49 (d, 9H).

LC/MS (m/z) [M+1]⁺ 669.9 (calculated for C₂₉H₂₈Cl₂F₃N₅O₄S, 669.12).

B.5-[3-Chloro-1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-onewas prepared from4-{5-[3-Chloro-1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester following general procedure H.

¹H NMR (400 MHz, CDCl₃): δ 7.90 (s, 1H), 7.86 (s, 1H), 7.71 (d, 1H),7.56 (d, 1H), 7.38 (d, 1H), 7.29 (d, 1H), 6.80 (d, 1H), 5.71 (s, 2H),4.79-4.74 (m, 1H), 3.79-3.74 (m, 2H), 3.70-3.66 (m, 0.5H), 3.61-3.57 (m,0.5H), 3.54-3.47 (m, 0.5H), 3.38-3.30 (m, 1H), 3.27-3.16 (m, 1.5H),3.05-2.93 (m, 2H).

LC/MS (m/z) [M+1]⁺ 570.2 (calculated for C₂₄H₂₀Cl₂F₃N₅O₂S, 569.07).

Example 1884-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]morpholine-2-carboxylicacid

4-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]morpholine-2-carboxylicacid was prepared from5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]2-methylsulfanyl-thiazol-4-oneand morpholine-2-carboxylic acid following General Procedure C.

¹H NMR (400 MHz, CD₃OD) δ 8.29 (dd, 1H), 8.15 (d, 1H), 8.06 (s, 1H),7.91 (s, 1H), 7.80 (d, 1H), 7.69 (ddd, 1H), 7.60 (dd, 1H), 6.86 (d, 1H),5.98 (s, 2H), 4.76 (m, 1/2H), 4.44 (m, 1/2H), 4.30-4.37 (1H), 4.01-4.19(1H), 3.67-3.86 (4H).

LC/MS (m/z) [M+1]⁺ 585.1 (calculated for C₂₆H₁₉F₆N₄O₃S, 584.1).

Example 1891-[5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-4-(S)-fluoro-L-proline

1-[5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-4-(S)-fluoro-L-prolinewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 4-(S)—Fluoro-pyrrolidine-2-(S)-carboxylic acid following GeneralProcedure C.

¹H NMR (400 MHz, CDCl₃) δ 10.61 (br s, 1H), 8.14 (d, 1H), 7.86 (m, 1H),7.78 (m, 1H), 7.67 (m, 1H), 7.41 (t, 1H), 7.31 (dd, 1H), 7.24 (m, 1H),6.63 (t, 1H), 5.71 (d, 2H), 5.38 (m, 1H), 4.91 (dd, 1H), 3.88-4.31 (2H),2.50-3.69 (2H).

LC/MS (m/z) [M+1]⁺ 553.0 (calculated for C₂₄H₁₇ClF₄N₄O₃S, 552.1).

Example 190 Methyl1-[5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]piperidine-4-carboxylate

Methyl1-[5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]piperidine-4-carboxylatewas prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand Piperidine-4-carboxylic acid methyl ester following GeneralProcedure C.

¹H NMR (400 MHz, CDCl₃) δ 8.22 (s, 1H), 7.99 (br s, 2H), 7.95 (s, 1H),7.63 (d, 1H), 7.56 (dd, 1H), 7.32 (d, 1H), 7.56 (dd, 1H), 7.32 (d, 1H),6.82 (d, 1H), 5.89 (s, 2H), 4.67 (m, 1/2H), 3.92 (s, 3H), 3.89 (m,1/2H), 3.44-3.60 (2H), 2.79 (m, 1H), 2.16 (m, 2H), 1.88-1.98 (3H).

LC/MS (m/z) [M+1]⁺ 597.0 (calculated for C₂₇H₂₂F₈N₄O₃S, 596.1).

Example 1911-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-3-iodo-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]piperidine-4-carboxylicacid

A. 3-Iodo-1H-indazole-5-carbaldehyde

To a solution of 1H-indazole-5-carboxaldehyde (670.2 mg, 4.59 mmol) inDMF (5 mL) were added iodine (2.33 g, 9.17 mmol) and potassium hydroxidepellets (1.03 g, 18.36 mmol) at room temperature under stirring. After 4h, the mixture was quenched with aqueous Na₂S₂O₃ solution and extractedwith EtOAc. The combined extracts were washed with brine, dried, andevaporated to afford the title product.

¹H NMR (400 MHz, CD₃OD) δ10.05 (s, 1H), 8.10 (m, 1H), 7.99 (dd, 1H),7.65 (d, 1H).

LC/MS (m/z) [M+1]⁺ 272.9 (calculated for C₈H₅₁N₂O, 271.94).

B. 1-(2,4-Bis-trifluoromethyl-benzyl)-3-iodo-1H-indazole-5-carbaldehydewas prepared from 3-Iodo-1H-indazole-5-carbaldehyde and1-Bromomethyl-2,4-bis-trifluoromethyl-benzene following GeneralProcedure A.

¹H NMR (400 MHz, CDCl₃) δ 10.10 (s, 1H), 8.09 (m, 1H), 8.01 (d, 1H),7.99 (d, 1H), 7.67 (d, 1H), 7.35 (d, 1H), 6.92 (d, 1H), 5.91 (s, 2H).

LC/MS (m/z) [M+F1]⁺ 498.9 (calculated for C₁₇H₉F₆₁N₂O, 497.97).

C.1-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-3-iodo-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]piperidine-4-carboxylicacid was prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-iodo-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand Piperidine-4-carboxylic acid following general procedure C.

¹H NMR (400 MHz, CDCl₃) δ 7.98 (br s, 1H), 7.94 (s, 1H), 7.71 (s, 1H),7.66 (d, 1H), 7.60 (dd, 1H), 7.28 (m, 1H), 6.90 (d, 1H), 5.89 (s, 2H),4.68 (m, 1/2H), 3.90 (m, 1/2H), 3.46-3.62 (2H), 2.11-2.84 (2H),1.49-2.02 (4H).

LC/MS (m/z) [M+1]⁺ 709.0 (calculated for C₂₆H₁₉F₆₁N₄O₃S, 708.43).

Example 1925-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(2-(R),4-dimethylpiperazin-1-yl)-1,3-thiazol-4(5H)-one

5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(2-(R),4-dimethylpiperazin-1-yl)-1,3-thiazol-4(5H)-onewas prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 1,3-(R)-Dimethyl-piperazine following general procedure C.

¹H NMR (400 MHz, CD₃OD) δ 8.23 (s, 1H), 8.04 (s, 1H), 8.03 (s, 1H), 7.78(s, 1H), 7.76 (d, 1H), 7.60 (dd, 1H), 7.53 (d, 1H), 6.84 (d, 1H), 5.92(s, 2H), 4.91 (m, 1/2H), 4.56 (d, 1/2H), 4.13 (br s, 1/2H), 3.72 (m,1H), 3.49 (m, 1/2H), 2.79-2.99 (2H), 2.31 (s, 3H), 2.30 (m, 1H), 2.14(m, 1H), 1.46 (dd, 3H).

LC/MS (m/z) [M+1]⁺ 568.1 (calculated for C₂₆H₂₃F₆N₅OS, 567.1).

Example 1935-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(2-(R),4-dimethylpiperazin-1-yl)-1,3-thiazol-4(5H)-one

5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(2(R),4-dimethylpiperazin-1-yl)-1,3-thiazol-4(5H)-onewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 1,3-(R)-Dimethyl-piperazine following general procedure C.

¹H NMR (400 MHz, CDCl₃) δ 8.18 (s, 1H), 7.96 (s, 1H), 7.92 (s, 1H), 7.70(d, 1H), 7.53 (dd, 1H), 7.33 (dd, 1H), 7.30 (d, 1H), 6.66 (d, 1H), 5.77(s, 2H), 5.10 (br s, 1/2H), 4.74 (d, 1/2H), 4.03 (br s, 1/2H), 3.76 (m,1/2H), 3.47-3.61 (1H), 2.95 (m, 1H), 2.80 (m, 1H), 2.37 (m, 1H), 2.35(s, 3H), 2.19 (m, 1H), 1.49 (dd, 3H).

LC/MS (m/z) [M+1]⁺ 534.1 (calculated for C₂₅H₂₃ClF₃N₅OS, 533.13).

Example 1944-[5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]morpholine-3-(R)-carboxylicacid

4-[5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]morpholine-3-(R)-carboxylicacid was prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand Morpholine-3-(R)-carboxylic acid following general procedure C.

¹H NMR (400 MHz, CD₃OD) δ 8.10 (s, 1H), 7.80 (d, 1H), 7.68 (s, 1H), 7.57(d, 1H), 7.39 (d, 1H), 7.35 (d, 1H), 7.32 (d, 1H), 6.61 (d, 1H), 5.68(s, 2H), 5.20 (m, 1/2H), 4.56 (m, 1/2H), 4.38-4.53 (1H), 3.55-4.02 (5H).

LC/MS (m/z) [M+1]⁺ 551.2 (calculated for C₂₄H₁₈ClF₃N₄O₄S, 550.07).

Example 1955-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3-(R)-(hydroxymethyl)-4-methylpiperazin-1-yl]-1,3-thiazol-4(5H)-one

To 4 mL of CH₂Cl₂ was added5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3-(R)-(hydroxymethyl)-piperazin-1-yl]-1,3-thiazol-4(5H)-one(Example 139, 50 mg), followed by 50 mg of 37% HCHO. The mixture wasstirred at room temperature for 20 min, then 50 mg of NaBH(OAc)₃ wasadded. The reaction mixture was kept stirring for 1 h and partitionedbetween CH₂Cl₂ and water. The combined organic extracts were washed withbrine, dried, and evaporated. The residue was purified by flash columnchromatography on silica gel, eluting with EtOAc to MeOH/EtOAc (10/90)to afford the title product.

¹H NMR (400 MHz, CD₃OD) δ 8.22 (s, 1H), 8.04 (s, 1H), 8.02 (s, 1H), 7.78(s, 1H), 7.77 (d, 1H), 7.59 (d, 1H), 7.52 (d, 1H), 6.84 (d, 1H), 5.92(s, 2H), 4.51-4.69 (1H), 3.56-3.93 (4H), 3.49 (m, 1H), 3.00 (m, 1H),2.30-2.55 (5H).

LC/MS (m/z) [M+1]⁺ 584.1 (calculated for C₂₆H₂₃F₆N₅O₂S, 583.15).

Example 1965-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3-(R)-(hydroxymethyl)-4-methylpiperazin-1-yl]-1,3-thiazol-4(5H)-one

5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3-(R)-(hydroxymethyl)-4-methylpiperazin-1-yl]-1,3-thiazol-4(5H)-onewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-oneand formaldehyde following procedure used for compound of example 195.

¹H NMR (400 MHz, CDCl₃) δ 8.19 (d, 1H), 7.96 (s, 1H), 7.93 (s, 1H), 7.71(d, 1H), 7.53 (dd, 1H), 7.33 (d, 1H), 7.31 (d, 1H), 6.66 (d, 1H), 5.78(d, 2H), 4.72 (m, 1H), 3.91 (dd, 1H), 3.40-3.80 (4H), 2.98 (m, 1H),2.30-2.53 (5H).

LC/MS (m/z) [M+1]⁺ 550.1 (calculated for C₂₅H₂₃ClF₃N₅O₂S, 549.12).

Example 1975-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(3-hydroxy-4,7-dihydroisoxazolo[5,4-c]pyridin-6(5H)-yl)-1,3-thiazol-4(5H)-one

5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(3-hydroxy-4,7-dihydroisoxazolo[5,4-c]pyridin-6(5H)-yl)-1,3-thiazol-4(5H)-onewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 4,5,6,7-Tetrahydro-isoxazolo[5,4-c]pyridin-3-ol following generalprocedure C.

¹H NMR (400 MHz, CD₃OD) δ 8.26 (s, 1H), 8.14 (s, 1H), 7.91 (d, 1H), 7.80(d, 1H), 7.69 (dd, 1H), 7.57 (d, 1H), 7.49 (dd, 1H), 6.69 (d, 1H), 5.87(s, 2H), 5.05 (s, 1H), 4.84 (s, 1H), 4.28 (t, 1/2H), 3.98 (t, 3/2H),2.68 (t, 1H), 2.63 (t, 1H).

LC/MS (m/z) [M+1]⁺ 560.0 (calculated for C₂₅H₁₇ClF₃N₅O₃S, 559.07).

Example 1981-[5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-1,2,3,6-tetrahydropyridine-4-carboxylicacid

1-[5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-1,2,3,6-tetrahydropyridine-4-carboxylicacid was prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 1,2,3,6-Tetrahydro-pyridine-4-carboxylic acid following generalprocedure C.

¹H NMR (400 MHz, CD₃OD) δ 8.26 (m, 1H), 8.14 (s, 1H), 7.90 (d, 1H), 7.80(d, 1H), 7.69 (d, 1H), 7.58 (d, 1H), 7.49 (dd, 1H), 6.98 (m, 1H), 6.69(d, 1H), 5.87 (s, 2H), 4.63 (m, 2H), 4.42 (m, 1/2H), 4.15 (m, 1/2H),3.86 (t, 1H), 2.55-2.66H).

LC/MS (m/z) [M+1]⁺ 547.0 (calculated for C₂₅H₁₈ClF₃N₄O₃S, 546.07).

Example 1995-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[4-(2-methoxyethyl)-2-(R)-methylpiperazin-1-yl]-1,3-thiazol-4(5H)-one

5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[4-(2-methoxyethyl)-2-(R)-methylpiperazin-1-yl]-1,3-thiazol-4(5H)-onewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 1-(2-Methoxy-ethyl)-3-(R)-methyl-piperazine following generalprocedure C.

¹H NMR (400 MHz, CD₃OD) δ 8.24 (s, 1H), 8.09 (s, 1H), 7.84 (s, 1H), 7.80(d, 1H), 7.65 (dd, 1H), 7.55 (d, 1H), 7.48 (dd, 1H), 6.68 (d, 1H), 5.85(s, 2H), 4.56 (d, 1/2H), 4.13 (m, 1/2H), 3.72 (m, 1H), 3.47-3.59 (3H),3.37 (s, 3H), 3.06 (dd, 1H), 2.96 (dd, 1H), 2.54-2.67 (2H), 2.39 (m,1H), 2.26 (m, 1H), 1.48 (dd, 3H).

LC/MS (m/z) [M+1]⁺ 578.2 (calculated for C₂₇H₂₇ClF₃N₅O₂S, 577.15).

Example 2005-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3-(S)-(hydroxymethyl)piperazin-1-yl]-1,3-thiazol-4(5H)-one

A.4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(S)-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester was prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 2-(S)—Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl esterfollowing general procedure C.

LC/MS (m/z) [M+1]⁺ 670.3 (calculated for C₃₀H₂₉F₆N₅O₄S, 669.18).

B.5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3-(S)-(hydroxymethyl)piperazin-1-yl]-1,3-thiazol-4(5H)-onewas prepared from4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(S)-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester following General Procedure H.

¹H NMR (400 MHz, CD₃OD) δ 8.27 (s, 1H), 8.14 (s, 1H), 8.06 (s, 1H), 7.94(s, 1H), 7.80 (d, 1H), 7.68 (d, 1H), 7.59 (d, 1H), 6.88 (d, 1H), 5.97(s, 2H), 4.83-4.94 (1H), 4.14 (m, 1H), 3.71-3.92 (3H), 3.51-3.68 (3H),3.35-3.46 (1H).

LC/MS (m/z) [M+1]⁺ 570.3 (calculated for C₂₅H₂₁F₆N₅O₂S, 569.13).

Example 2012-[2-(Aminomethyl)morpholin-4-yl]-5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazol-4(5H)-one

A.(4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-morpholin-2-ylmethyl)-carbamicacid tert-butyl ester was prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand Morpholin-2-ylmethyl-carbamic acid tert-butyl ester followingGeneral Procedure C.

LC/MS (m/z) [M+1]⁺ 670.3 (calculated for C₃₀H₂₉F₆N₅O₄S, 669.18).

B.2-[2-(Aminomethyl)morpholin-4-yl]-5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazol-4(5H)-onewas prepared from(4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-morpholin-2-ylmethyl)-carbamicacid tert-butyl ester following General Procedure H.

¹H NMR (400 MHz, CD₃OD) δ 8.28 (d, 1H), 8.15 (s, 1H), 8.06 (s, 1H), 7.93(s, 1H), 7.80 (d, 1H), 7.69 (dd, 1H), 7.60 (dd, 1H), 6.88 (d, 1H), 5.98(s, 2H), 4.70 (m, 1H), 4.16 (m, 1H), 3.01-3.99 (7H).

LC/MS (m/z) [M+1]⁺ 570.3 (calculated for C₂₅H₂₁F₆N₅O₂S, 569.13).

Example 2025-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3-(2,6-cis-dimethylmorpholin-4-yl)azetidin-1-yl]-1,3-thiazol-4(5H)-one

A. 3-(2,6-cis-Dimethyl-morpholin-4-A-azetidine-1-carboxylic acidtert-butyl ester

To a CH₂Cl₂ solution containing 1-Boc-azetidine (459.3 mg, 2.68 mmol)was added 2,6-cis-dimethylmorpholine (311 mg, 2.7 mmol). The mixture wasstirred for 20 min, NaBH(OAc)₃ (572.2 mg, 2.70 mmol) was added and theresulting mixture was kept stirring for 2 h. It was then partitionedbetween CH₂Cl₂ and water. The organic extracts were washed with brine,dried, and evaporated to afford the Boc-protected intermediate.

¹H NMR (400 MHz, CDCl₃) δ 3.92 (t, 2H), 3.83 (dd, 2H), 3.66-3.74 (2H),3.05 (m, 1H), 2.66 (d, 2H), 2.09 (d, 2H), 1.44 (s, 9H), 1.18 (d, 6H).

B. 4-Azetidin-3-yl-2,6-(cis)-dimethyl-morpholine was prepared as a TFAsalt from 3-(2,6-(cis)-Dimethyl-morpholin-4-yl)-azetidine-1-carboxylicacid tert-butyl ester following General Procedure H.

¹H NMR (400 MHz, CD₃OD) δ4.49 (m, 2H), 4.33 (m, 2H), 4.18 (m, 1H),3.85-3.93 (2H), 3.37 (d, 2H), 2.45 (t, 2H), 1.22 (d, 6H).

LC/MS (m/z) [M+1]⁺ 171.2 (calculated for C₉H₁₈N₂O, 170.14).

C.5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3-(2,6-cis-dimethylmorpholin-4-yl)azetidin-1-yl]-1,3-thiazol-4(5H)-onewas prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 4-Azetidin-3-yl-2,6-(cis)-dimethyl-morpholine following GeneralProcedure C.

¹H NMR (400 MHz, CDCl₃) δ 8.21 (d, 1H), 7.99 (s, 1H), 7.97 (s, 1H), 7.92(s, 1H), 7.63 (dd, 1H), 7.54 (dd, 1H), 7.32 (d, 1H), 6.81 (d, 1H), 5.89(s, 2H), 4.44 (dd, 1H), 4.30 (dd, 1H), 4.28 (dd, 1H), 4.19 (dd, 1H),3.70 (m, 2H), 3.45 (m, 1H), 2.67 (m, 2H), 1.76 (dd, 1H), 1.73 (dd, 1H),1.20 (d, 6H).

LC/MS (m/z) [M+1]⁺ 624.5 (calculated for C₂₉H₂₇F₆N₅O₂S, 623.18).

Example 2035-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3-(2,6-cis-dimethylmorpholin-4-yl)azetidin-1-yl]-1,3-thiazol-4(5H)-one

5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3-(2,6-cis-dimethylmorpholin-4-yl)azetidin-1-yl]-1,3-thiazol-4(5H)-onewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 4-Azetidin-3-yl-2,6-(cis)-dimethyl-morpholine following GeneralProcedure C.

¹H NMR (400 MHz, CDCl₃) δ 8.19 (d, 1H), 7.95 (m, 1H), 7.92 (s, 1H), 7.71(d, 1H), 7.52 (dd, 1H), 7.30-7.35 (2H), 6.65 (d, 1H), 5.79 (s, 2H), 4.44(m, 1H), 4.30 (dd, 1H), 4.27 (dd, 1H), 4.18 (m, 1H), 3.70 (m, 2H), 3.45(m, 1H), 2.67 (m, 2H), 1.76 (dd, 1H), 1.73 (dd, 1H), 1.20 (d, 6H).

LC/MS (m/z) [M+1]⁺ 590.4 (calculated for C₂₈H₂₇ClF₃N₅O₂S, 589.15).

Example 2045-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(3-morpholin-4-ylazetidin-1-yl)-1,3-thiazol-4(5H)-one

5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(3-morpholin-4-ylazetidin-1-yl)-1,3-thiazol-4(5H)-onewas prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 4-Azetidin-3-yl-morpholine following General Procedure C.

¹H NMR (400 MHz, CDCl₃) δ 8.22 (d, 1H), 7.99 (d, 1H), 7.97 (m, 1H), 7.93(s, 1H), 7.63 (dd, 1H), 7.54 (dd, 1H), 7.32 (d, 1H), 6.81 (d, 1H), 5.89(s, 2H), 4.45 (m, 1H), 4.27-4.33 (2H), 4.18 (m, 1H), 3.77 (t, 4H), 3.49(m, 1H), 2.45 (m, 4H).

LC/MS (m/z) [M+1]⁺ 596.4 (calculated for C₂₇H₂₃F₆N₅O₂S, 595.15).

Example 2055-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(3-morpholin-4-ylazetidin-1-yl)-1,3-thiazol-4(5H)-one

5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(3-morpholin-4-ylazetidin-1-yl)-1,3-thiazol-4(5H)-onewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 4-Azetidin-3-yl-morpholine following General Procedure C.

¹H NMR (400 MHz, CDCl₃) δ 8.19 (d, 1H), 7.95 (m, 1H), 7.92 (s, 1H), 7.71(d, 1H), 7.52 (dd, 1H), 7.33 (dd, 1H), 7.31 (d, 1H), 6.65 (d, 1H), 5.79(s, 2H), 4.45 (dd, 1H), 4.26-4.32 (2H), 4.18 (dd, 1H), 3.77 (t, 4H),3.48 (m, 1H), 2.45 (m, 4H).

LC/MS (m/z) [M+1]⁺ 562.3 (calculated for C₂₆H₂₃ClF₃N₅O₂S, 561.12).

Example 2065-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3-(S)-(hydroxymethyl)piperazin-1-yl]-1,3-thiazol-4(5H)-one

A.4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(S)-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester was prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 2-(S)—Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl esterfollowing General Procedure C.

LC/MS (m/z) [M+1]⁺ 636.3 (calculated for C₂₄H₂₁ClF₃N₅O₂S, 635.16).

B.5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3-(S)-(hydroxymethyl)piperazin-1-yl]-1,3-thiazol-4(5H)-onewas prepared from4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(S)-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester following General Procedure H.

¹H NMR (400 MHz, CDCl₃) δ 8.15 (d, 1H), 7.92 (s, 1H), 7.87 (d, 1H), 7.70(dd, 1H), 7.49 (dd, 1H), 7.32 (m, 1H), 7.27 (dd, 1H), 6.65 (dd, 1H),5.74 (d, 2H), 4.73 (d, 1H), 3.74 (m, 2H), 3.46-3.69 (2H), 3.13-3.37(2H), 2.92-3.07 (2H).

LC/MS (m/z) [M+1]⁺ 536.4 (calculated for C₂₄H₂₁ClF₃N₅O₂S, 535.11).

Example 2075-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[4-tert-butyl-3-(R)-(hydroxymethyl)piperazin-1-yl]-1,3-thiazol-4(5H)-one

5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[4-tert-butyl-3-(R)-(hydroxymethyl)piperazin-1-yl]-1,3-thiazol-4(5H)-onewas obtained from4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester using General Procedure H.

¹H NMR (400 MHz, CDCl₃) δ 8.22 (dd, 1H), 7.98-8.00 (2H), 7.94 (s, 1H),7.63 (d, 1H), 7.56 (dt, 1H), 7.32 (d, 1H), 6.81 (d, 1H), 5.89 (s, 2H),4.80 (d, 1H), 3.72 (dd, 1H), 2.89-3.52 (7H), 1.19-1.22 (9H).

LC/MS (m/z) [M+1]⁺ 626.5 (calculated for C₂₉H₂₉F₆N₅O₂S, 625.19).

Example 2085-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3-(R)-(methoxymethyl)piperazin-1-yl]-1,3-thiazol-4(5H)-one

A.4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-methoxymethyl-piperazine-1-carboxylicacid tert-butyl ester was prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 2-(R)-Methoxymethyl-piperazine-1-carboxylic acid tert-butyl esterfollowing General Procedure C.

LC/MS (m/z) [M+1]⁺ 650.6 (calculated for C₃₀H₃₁ClF₃N₅O₄S, 649.17).

B.5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3-(R)-(methoxymethyl)piperazin-1-yl]-1,3-thiazol-4(5H)-onewas prepared from4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-methoxymethyl-piperazine-1-carboxylicacid tert-butyl ester following General Procedure H.

¹H NMR (400 MHz, CDCl₃) δ 8.18 (s, 1H), 7.95 (s, 1H), 7.91 (d, 1H), 7.71(d, 1H), 7.52 (dd, 1H), 7.33 (dd, 1H), 7.30 (d, 1H), 6.66 (d, 1H), 5.77(s, 2H), 4.81 (m, 1H), 3.81 (d, 1H), 3.43-3.71 (5H), 3.39 (d, 3H),3.02-3.36 (2H).

LC/MS (m/z) [M+1]⁺ 550.5 (calculated for C₂₅H₂₃ClF₃N₅O₂S, 549.12).

Example 2095-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3-(S)-(methoxymethyl)piperazin-1-yl]-1,3-thiazol-4(5H)-one

A.4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(S)-methoxymethyl-piperazine-1-carboxylicacid tert-butyl ester was prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 2-(S)-Methoxymethyl-piperazine-1-carboxylic acid tert-butyl esterfollowing General Procedure C.

LC/MS (m/z) [M+1]⁺ 650.6 (calculated for C₃₀H₃₁ClF₃N₅O₄S, 649.17).

B.5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3-(S)-(methoxymethyl)piperazin-1-yl]-1,3-thiazol-4(5H)-onewas prepared from4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(S)-methoxymethyl-piperazine-1-carboxylicacid tert-butyl ester following General Procedure H.

¹H NMR (400 MHz, CDCl₃) δ 8.19 (dd, 1H), 7.97 (br s, 1H), 7.93 (s, 1H),7.71 (d, 1H), 7.54 (dt, 1H), 7.33 (d, 1H), 7.31 (d, 1H), 6.66 (d, 1H),5.79 (s, 2H), 4.79 (d, 1H), 3.74 (m, 1H), 3.40-3.51 (2H), 3.39 (d, 3H),3.02-3.35 (4H), 2.94 (m, 1H).

LC/MS (m/z) [M+1]⁺ 550.5 (calculated for C₂₅H₂₃ClF₃N₅O₂S, 549.12).

Example 2105-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3-(R)-(methoxymethyl)piperazin-1-yl]-1,3-thiazol-4(5H)-one

A.4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-methoxymethyl-piperazine-1-carboxylicacid tert-butyl ester was prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 2-(R)-Methoxymethyl-piperazine-1-carboxylic acid tert-butyl esterfollowing General Procedure C.

LC/MS (m/z) [M+1]⁺ 684.6 (calculated for C₃₁H₃₁F₆N₅O₄S, 683.20).

B.5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3-(R)-(methoxymethyl)piperazin-1-yl]-1,3-thiazol-4(5H)-onewas prepared from4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-methoxymethyl-piperazine-1-carboxylicacid tert-butyl ester following General Procedure H.

¹H NMR (400 MHz, CD₃OD) δ 8.26 (s, 1H), 8.11 (d, 1H), 8.05 (s, 1H), 7.96(s, 1H), 7.80 (d, 1H), 7.65 (d, 1H), 7.58 (d, 1H), 6.88 (d, 1H), 5.94(s, 2H), 4.80 (t, 1H), 4.24 (m, 1H), 3.52-4.02 (7H), 3.49 (d, 3H).

LC/MS (m/z) [M+1]⁺ 584.5 (calculated for C₂₆H₂₃F₆N₅O₂S, 583.15).

Example 2115-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3-(S)-(methoxymethyl)piperazin-1-yl]-1,3-thiazol-4(5H)-one

A.4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(S)-methoxymethyl-piperazine-1-carboxylicacid tert-butyl ester was prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 2-(S)-Methoxymethyl-piperazine-1-carboxylic acid tert-butyl esterfollowing General Procedure C.

LC/MS (m/z) [M+1]⁺ 684.6 (calculated for C₃₁H₃₁F₆N₅O₄S, 683.20).

B.5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3-(S)-(methoxymethyl)piperazin-1-yl]-1,3-thiazol-4(5H)-onewas prepared from4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(S)-methoxymethyl-piperazine-1-carboxylicacid tert-butyl ester following General Procedure H.

¹H NMR (400 MHz, CD₃OD) δ 8.21 (s, 1H), 8.04 (br s, 2H), 7.89 (s, 1H),7.76 (d, 1H), 7.60 (d, 1H), 7.52 (d, 1H), 6.84 (d, 1H), 5.90 (s, 2H),4.80 (m, 1H), 4.19 (br, 1H), 3.54-3.98 (7H), 3.49 (d, 3H).

LC/MS (m/z) [M+1]⁺ 584.5 (calculated for C₂₆H₂₃F₆N₅O₂S, 583.15).

Example 2125-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[2-(S)-(hydroxymethyl)morpholin-4-yl]-1,3-thiazol-4(5H)-one

5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[2-(S)-(hydroxymethyl)morpholin-4-yl]-1,3-thiazol-4(5H)-onewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand (S)-Morpholin-2-yl-methanol following General Procedure C.

¹H NMR (400 MHz, CDCl₃) δ 8.20 (dd, 1H), 7.98 (br s, 1H), 7.96 (s, 1H),7.72 (d, 1H), 7.54 (m, 1H), 7.34 (dd, 1H), 7.32 (d, 1H), 6.67 (d, 1H),5.79 (s, 2H), 4.82 (m, 1H), 4.12 (m, 1H), 3.25-3.85 (7H).

LC/MS (m/z) [M+1]⁺ 537.4 (calculated for C₂₄H₂₀ClF₃N₄O₃S, 536.09).

Example 213 Methyl{1-[5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-5-(R)-(hydroxymethyl)pyrrolidin-3-(R)-yl}carbamate

Methyl{1-[5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-5-(R)-(hydroxymethyl)pyrrolidin-3-(R)-yl}carbamatewas prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand (5-(R)-Methyl-pyrrolidin-3-(R)-yl)-carbamic acid methyl esterfollowing General Procedure C.

¹H NMR (400 MHz, CD₃OD) δ 8.29 (dd, 1H), 8.14 (m, 1H), 8.06 (br s, 1H),7.88 (s, 1H), 7.79 (d, 1H), 7.68 (m, 1H), 7.60 (d, 1H), 6.86 (d, 1H),5.98 (s, 2H), 4.02-4.45 (3H), 3.69 (m, 1H), 3.66 (s, 3H), 3.50 (m, 1H),2.59 (m, 1H), 2.10 (m, 1H).

LC/MS (m/z) [M+1]⁺ 628.1 (calculated for C₂₇H₂₃F₆N₅O₄S, 627.14).

Example 214(1R,6R)-7-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-4-oxa-2,7-diazabicyclo[4.2.1]nonan-3-one

(1R,6R)-7-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-4-oxa-2,7-diazabicyclo[4.2.1]nonan-3-onewas obtained from Methyl{1-[5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-5-(R)-(hydroxymethyl)pyrrolidin-3-(R)-yl}carbamate(example 213) following General Procedure H.

¹H NMR (400 MHz, CDCl₃) δ 8.22 (m, 1H), 7.98-7.97 (m, 3H), 7.63 (d, 1H),7.55 (d, 1H), 7.33 (d, 1H), 6.82 (dd, 1H), 6.57 (d, 1H), 5.88 (s, 2H),5.06 (s, 1H), 4.80-4.72 (m, 1H) 4.15-3.78 (m, 4H), 2.48-2.15 (m, 2H).

LC/MS (m/z) [M+1]⁺ 595.1 (calculated for C₂₆H₁₉F₆N₅O₃S, 596.1).

Example 2155-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[4-(cyclopropylcarbonyl)-3-(R)-(hydroxymethyl)piperazin-1-yl]-1,3-thiazol-4(5H)-one

5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[4-(cyclopropylcarbonyl)-3-(R)-(hydroxymethyl)piperazin-1-yl]-1,3-thiazol-4(5H)-onewas prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one(example 139) and Cyclopropanecarbonyl chloride.

¹H NMR (400 MHz, CDCl₃) δ 8.19 (s, 1H), 7.99 (br s, 2H), 7.92 (d, 1H),7.63 (d, 1H), 7.50 (d, 1H), 7.28 (d, 1H), 6.82 (t, 1H), 5.87 (s, 2H),4.45-5.08 (3H), 3.00-4.26 (6H), 1.81 (m, 1H), 1.05 (m, 2H), 0.87 (m,2H).

LC/MS (m/z) [M+1]⁺ 638.5 (calculated for C₂₉H₂₅F₆N₅O₃S, 637.16).

Example 216 Methyl4-[5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-2-(R)-(hydroxymethyl)piperazine-1-carboxylate

Methyl4-[5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-2-(R)-(hydroxymethyl)piperazine-1-carboxylatewas prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one(example 139) and Methyl chloroformate.

¹H NMR (400 MHz, CDCl₃) δ 8.18-8.20 (1H), 7.98 (s, 1H), 7.91-7.94 (1H),7.88-7.90 (1H), 7.62 (d, 1H), 7.50 (dd, 1H), 7.29 (d, 1H), 6.80-6.84(1H), 5.84-5.87 (2H), 4.85 (dd, 1H), 4.43 (br s, 1H), 4.05-4.29 (2H),3.23-3.84 (8H).

LC/MS (m/z) [M+1]⁺ 628.5 (calculated for C₂₇H₂₃F₆N₅O₄S, 627.14).

Example 2171-[2,4-Bis(trifluoromethyl)benzyl]-5-({2-[3-(R)-(hydroxymethyl)piperazin-1-yl]-4-oxo-1,3-thiazol-5(4H)-ylidene}methyl)-1H-indazole-3-carbonitrile

A.1-(2,4-Bis-trifluoromethyl-benzyl)-5-formyl-1H-indazole-3-carbonitrile

A 5 mL microwave reaction vessel was charged with1-(2,4-Bis-trifluoromethyl-benzyl)-3-iodo-1H-indazole-5-carbaldehyde(300 mg, 0.6 mmol), copper (I) cyanide (135 mg, 1.5 mmol), andN,N-dimethylformamide (4 mL). The vessel was sealed and subjected tomicrowave irradiation at 185° C. for 15 min. The reaction mixture waspartitioned between EtOAc and water. The organic layers were washed withbrine, dried over Na₂SO₄, and evaporated. The crude residue was purifiedby flash column chromatography on silica gel, eluting with EtOAc/hexanes(1:4 v/v), to afford the title compound as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 10.15 (s, 1H), 8.44 (s, 1H), 8.30 (s, 1H),8.07 (m, 1H), 7.74 (m, 1H), 7.51 (d, 1H), 7.00 (d, 1H), 5.96 (s, 2H).

B.4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-cyano-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester was prepared from1-(2,4-Bis-trifluoromethyl-benzyl)-5-(2-ethylsulfanyl-4-oxo-4H-thiazol-5-ylidenemethyl)-1H-indazole-3-carbonitrileand 2-(R)—Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl esterfollowing General Procedure C.

LC/MS (m/z) [M+1]⁺ 695.3 (calculated for C₃₁H₂₈F₆N₆O₄S, 694.18).

C.1-[2,4-Bis(trifluoromethyl)benzyl]-5-({2-[3-(R)-(hydroxymethyl)piperazin-1-yl]-4-oxo-1,3-thiazol-5(4H)-ylidene}methyl)-1H-indazole-3-carbonitrilewas prepared from4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-cyano-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester following General Procedure H.

¹H NMR (400 MHz, CD₃OD) δ 8.07 (s, 1H), 7.89 (d, 1H), 7.86 (d, 1H), 7.78(d, 1H), 7.74 (d, 1H), 7.71 (br s, 1H), 7.13 (d, 1H), 6.04 (s, 2H), 4.84(m, 1H), 4.19 (m, 1H), 3.42-3.98 (7H).

LC/MS (m/z) [M+1]⁺ 595.2 (calculated for C₂₆H₂₀F₆N₆O₂S, 594.1).

Example 2181-[2,4-Bis(trifluoromethyl)benzyl]-5-({2-[3-(S)-(hydroxymethyl)piperazin-1-yl]-4-oxo-1,3-thiazol-5(4H)-ylidene}methyl)-1H-indazole-3-carbonitrile

A.4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-cyano-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(S)-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester was prepared from1-(2,4-Bis-trifluoromethyl-benzyl)-5-(2-ethylsulfanyl-4-oxo-4H-thiazol-5-ylidenemethyl)-1H-indazole-3-carbonitrileand 2-(S)—Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl esterfollowing General Procedure C.

LC/MS (m/z) [M+1]⁺ 695.3 (calculated for C₃₁H₂₈F₆N₆O₄S, 694.18).

B.1-[2,4-Bis(trifluoromethyl)benzyl]-5-({2-[3-(S)-(hydroxymethyl)piperazin-1-yl]-4-oxo-1,3-thiazol-5(4H)-ylidene}methyl)-1H-indazole-3-carbonitrilewas prepared from4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-cyano-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(S)-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester following General Procedure H.

¹H NMR (400 MHz, CD₃OD) δ 8.07 (s, 1H), 7.86 (d, 1H), 7.83 (d, 1H), 7.74(d, 1H), 7.67 (d, 1H), 7.66 (d, 1H), 7.12 (d, 1H), 6.03 (s, 2H), 4.86(m, 1H), 4.16 (m, 1H), 3.41-3.98 (7H).

LC/MS (m/z) [M+1]⁺ 595.2 (calculated for C₂₆H₂₀F₆N₆O₂S, 594.1).

Example 2195-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(3,3,4-trimethylpiperazin-1-yl)-1,3-thiazol-4(5H)-one

5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(3,3,4-trimethylpiperazin-1-yl)-1,3-thiazol-4(5H)-onewas prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 1,2,2-Trimethyl-piperazine following General Procedure C.

¹H NMR (400 MHz, CDCl₃) δ 8.28 (d, 1H), 8.16 (s, 1H), 8.06 (s, 1H), 7.96(s, 1H), 7.80 (d, 1H), 7.70 (d, 1H), 7.61 (d, 1H), 6.89 (d, 1H), 5.98(s, 2H), 3.49-4.21 (6H), 2.91 (s, 3H), 1.29-1.60 (6H).

LC/MS (m/z) [M+1]⁺ 582.1 (calculated for C₂₇H₂₅F₆N₅OS, 581.1).

Example 2204-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-N-tert-butylpiperazine-2-(S)-carboxamide

4-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-N-tert-butylpiperazine-2-(S)-carboxamidewas prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand piperazine-2-(S)-carboxylic acid tert-butylamide following GeneralProcedure C.

¹H NMR (400 MHz, CD₃OD) δ 8.25-8.27 (1H), 8.11-8.13 (1H), 8.05 (1H),7.94 (s, 1H), 7.78 (d, 1H), 7.66 (m, 1H), 7.57 (d, 1H), 6.87 (d, 1H),5.95 (s, 2H), 4.71-4.95 (1H), 4.30 (m, 1H), 4.16 (m, 1H), 3.88 (m, 1H),3.62-3.80 (2H), 3.48 (m, 1H), 1.36-1.41 (9H).

LC/MS (m/z) [M+1]⁺ 639.1 (calculated for C₂₉H₂₈F₆N₆O₂S, 638.1).

Example 2215-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(3,3,4-trimethylpiperazin-1-yl)-1,3-thiazol-4(5H)-one

5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(3,3,4-trimethylpiperazin-1-yl)-1,3-thiazol-4(5H)-onewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 1,2,2-Trimethyl-piperazine following General Procedure C.

¹H NMR (400 MHz, CD₃OD) δ 8.25 (d, 1H), 8.15 (s, 1H), 7.96 (s, 1H), 7.81(d, 1H), 7.69 (d, 1H), 7.58 (dd, 1H), 7.49 (dd, 1H), 6.72 (d, 1H), 5.87(s, 2H), 3.19-3.62 (6H), 2.92 (s, 3H), 1.39-1.60 (6H).

LC/MS (m/z) [M+1]⁺ 548.1 (calculated for C₂₆H₂₅ClF₃N₅OS, 547.1).

Example 2221-[4-Chloro-2-(trifluoromethyl)benzyl]-5-{[4-oxo-2-(3,3,4-trimethylpiperazin-1-yl)-1,3-thiazol-5(4H)-ylidene]methyl}-1H-indazole-3-carbonitrile

1-[4-Chloro-2-(trifluoromethyl)benzyl]-5-{[4-oxo-2-(3,3,4-trimethylpiperazin-1-yl)-1,3-thiazol-5(4H)-ylidene]methyl}-1H-indazole-3-carbonitrilewas prepared from1-(4-Chloro-2-trifluoromethyl-benzyl)-5-(2-ethylsulfanyl-4-oxo-4H-thiazol-5-ylidenemethyl)-1H-indazole-3-carbonitrileand 1,2,2-Trimethyl-piperazine following General Procedure C.

¹H NMR (400 MHz, CD₃OD) δ 8.14 (br s, 1H), 7.98 (s, 1H), 7.84 (d, 1H),7.81 (s, 1H), 7.80 (d, 1H), 7.58 (dd, 1H), 7.00 (d, 1H), 5.97 (s, 2H),3.10-3.72 (6H), 2.91 (s, 3H), 1.38-1.58 (6H).

LC/MS (m/z) [M+1]⁺ 573.1 (calculated for C₂₇H₂₄ClF₃N₆OS, 572.1).

Example 2231-[4-Chloro-2-(trifluoromethyl)benzyl]-5-{[2-(4-methylpiperazin-1-yl)-4-oxo-1,3-thiazol-5(4H)-ylidene]methyl}-1H-indazole-3-carbonitrile

1-[4-Chloro-2-(trifluoromethyl)benzyl]-5-{[2-(4-methylpiperazin-1-yl)-4-oxo-1,3-thiazol-5(4H)-ylidene]methyl}-1H-indazole-3-carbonitrilewas prepared from1-(4-Chloro-2-trifluoromethyl-benzyl)-5-(2-ethylsulfanyl-4-oxo-4H-thiazol-5-ylidenemethyl)-1H-indazole-3-carbonitrileand 1-Methyl-piperazine following General Procedure C.

¹H NMR (400 MHz, CD₃OD) δ 8.00 (s, 1H), 7.86 (s, 1H), 7.83 (d, 1H), 7.76(br s, 2H), 7.57 (dd, 1H), 6.98 (d, 1H), 5.94 (s, 2H), 4.25 (m, 1H),3.92 (m, 1H), 3.67-3.78 (3H), 3.35-3.49 (3H), 3.02 (s, 3H).

LC/MS (m/z) [M+1]⁺ 545.2 (calculated for C₂₅H₂₀ClF₃N₆OS, 544.1).

Example 2241-[4-Chloro-2-(trifluoromethyl)benzyl]-5-({2-[4-(cyclopropylmethyl)piperazin-1-yl]-4-oxo-1,3-thiazol-5(4H)-ylidene}methyl)-1H-indazole-3-carbonitrile

1-[4-Chloro-2-(trifluoromethyl)benzyl]-5-({2-[4-(cyclopropylmethyl)piperazin-1-yl]-4-oxo-1,3-thiazol-5(4H)-ylidene}methyl)-1H-indazole-3-carbonitrilewas prepared from1-(4-Chloro-2-trifluoromethyl-benzyl)-5-(2-ethylsulfanyl-4-oxo-4H-thiazol-5-ylidenemethyl)-1H-indazole-3-carbonitrileand 1-Cyclopropylmethyl-piperazine following General Procedure C.

¹H NMR (400 MHz, CD₃OD) δ 7.99 (s, 1H), 7.85 (s, 1H), 7.83 (d, 1H), 7.76(br s, 2H), 7.57 (dd, 1H), 6.98 (d, 1H), 5.94 (s, 2H), 3.16-4.30 (10H),1.18-1.40H), 0.80-0.86 (2H), 0.51 (m, 2H).

LC/MS (m/z) [M+1]⁺ 585.2 (calculated for C₂₈H₂₄ClF₃N₆OS, 584.1).

Example 225(5Z)-5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[(3S,4S)-3-hydroxy-4-morpholin-4-ylpyrrolidin-1-yl]-1,3-thiazol-4(5H)-one

5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[(3S,4S)-3-hydroxy-4-morpholin-4-ylpyrrolidin-1-yl]-1,3-thiazol-4(5H)-onewas prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 4-(3S,4S)-Morpholin-4-yl-pyrrolidin-3-ol following General ProcedureC.

¹H NMR (400 MHz, DMSO-d₆) δ 8.38 (m, 1H), 8.16 (m, 1H), 8.12 (s, 1H),7.98 (d, 1H), 7.84 (m, 1H), 7.82 (d, 1H), 7.71 (m, 1H), 6.92 (dd, 1H),5.99 (s, 2H), 4.86-5.00 (2H), 4.25 (m, 1H), 4.05-4.20 (2H), 3.80-4.05(5H), 3.71 (m, 1H), 3.55 (m, 1H), 3.19-3.50 (2H).

LC/MS (m/z) [M+1]⁺ 626.2 (calculated for C₂₈H₂₅F₆N₅O₃S, 625.14).

Example 226(2R)-4-[5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-N-methylpiperazine-2-carboxamide

(2R)-4-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-N-methylpiperazine-2-carboxamidewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand (2R)-piperazine-2-carboxylic acid methylamide following GeneralProcedure C.

¹H NMR (400 MHz, CD₃OD) δ 8.15 (d, 1H), 7.99 (d, 1H), 7.85 (d, 1H), 7.76(d, 1H), 7.53 (d, 1H), 7.44 (s, 1H), 7.43 (s, 1H), 6.64 (d, 1H), 5.74(m, 2H), 5.04 (m, 1/2H), 4.77 (m, 1/2H), 4.53 (m, 1/2H), 4.41 (m, 1H),4.20 (m, 1/2H), 3.94 (m, 1H), 3.67-3.87 (2H), 3.58 (m, 1H), 2.87 (m,3H).

LC/MS (m/z) [M+1]⁺ 563.1 (calculated for C₂₅H₂₂ClF₃N₆O₂S, 562.12).

Example 227(2R)-4-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-N-methylpiperazine-2-carboxamide

(2R)-4-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-N-methylpiperazine-2-carboxamidewas prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand (2R)-piperazine-2-carboxylic acid methylamide following GeneralProcedure C.

¹H NMR (400 MHz, CD₃OD) δ 8.17 (d, 1H), 8.02 (s, 1H), 8.00 (d, 1H), 7.85(d, 1H), 7.75 (d, 1H), 7.56 (d, 1H), 7.48 (m, 1H), 6.82 (d, 1H), 5.86(m, 2H), 5.07 (m, 1/2H), 4.78 (m, 1/2H), 4.53 (m, 1/2H), 4.41 (m, 1H),4.21 (m, 1/2H), 3.94 (m, 1H), 3.67-3.87 (2H), 3.58 (m, 1H), 2.87 (m,3H).

LC/MS (m/z) [M+1]⁺ 597.1 (calculated for C₂₆H₂₂F₆N₆O₂S, 596.14).

Example 228(2S)—N-tert-Butyl-4-[5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]piperazine-2-carboxamide

(2S)-4-[5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-N-methylpiperazine-2-carboxamidewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand (2S)-piperazine-2-carboxylic acid methylamide following GeneralProcedure C.

¹H NMR (400 MHz, CD₃OD) δ 8.21 (d, 1H), 8.05 (d, 1H), 7.89 (s, 1H), 7.77(s, 1H), 7.57 (d, 1H), 7.49 (d, 1H), 7.45 (d, 1H), 6.67 (d, 1H), 5.77(s, 2H), 4.99 (m, 1/2H), 4.71 (m, 1/2H), 4.20-4.44 (2H), 3.53-3.98 (4H),1.41 (m, 9H).

LC/MS (m/z) [M+1]⁺ 605.2 (calculated for C₂₈H₂₈Cl₃F₃N₆O₂S, 604.16).

Example 2295-({1-[2-Chloro-4-(1-hydroxy-1-methylethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3-(R)-(hydroxymethyl)piperazin-1-yl]-1,3-thiazol-4(5H)-one

A. 2-(3-Chloro-4-methyl-phenyl)-propan-2-ol

To a solution of 4-bromo-2-chlorotoluene (10 g, 48.7 mmol) in THF wasadded n-BuLi at −78° C. After the reaction mixture was stirred at −78°C. for 30 minutes, dry acetone was slowly added. The resulting contentwas maintained at −78° C. for 3 hours and slowly warmed up to RTovernight. The reaction mixture was then partitioned between ethylacetate and water. The ethyl acetate layer was then washed with brine,dried over Na₂SO₄, filtered, and the solvent evaporated in vacuo toyield a crude oil. The crude solid was purified via flash chromatography(30% EtOAc in n-hexane) yielded the title compound as an oil (7.2 g,80%)

¹H NMR (400 MHz, CDCl₃) δ 7.46 (d, 1H), 7.24 (dd, 1H), 7.16 (d, 1H),2.33 (s, 3H), 1.53 (s, 6H).

B. 2-(4-Bromomethyl-3-chloro-phenyl)-propan-2-ol was prepared followingprocedure described for example 9-A.

¹H NMR (400 MHz, CDCl₃) δ 7.53 (d, 1H), 7.40 (d, 1H), 7.35 (dd, 1H),4.59 (s, 2H), 1.56 (s, 6H).

C.4-(5-{1-[2-Chloro-4-(1-hydroxy-1-methyl-ethyl)-benzyl]-1H-indazol-5-ylmethylene}-4-oxo-4,5-dihydro-thiazol-2-yl)-2-(R)-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester was prepared from5-{1-[2-Chloro-4-(1-hydroxy-1-methyl-ethyl)-benzyl]-1H-indazol-5-ylmethylene}-2-ethylsulfanyl-thiazol-4-oneand 2-(R)—Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl esterfollowing General Procedure C.

LC/MS (m/z) [M+1]⁺ 626.4 (calculated for C₃₁H₃₆ClN₅O₅S, 625.21).

D.5-({1-[2-Chloro-4-(1-hydroxy-1-methylethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3-(R)-(hydroxymethyl)piperazin-1-yl]-1,3-thiazol-4(5H)-onewas prepared from4-(5-{1-[2-Chloro-4-(1-hydroxy-1-methyl-ethyl)-benzyl]-1H-indazol-5-ylmethylene}-4-oxo-4,5-dihydro-thiazol-2-yl)-2-(R)-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester following General Procedure H.

¹H NMR (400 MHz, CDCl₃) δ 8.16 (m, 1H), 7.95 (s, 1H), 7.94 (s, 1H),7.57-7.53 (m, 2H), 7.47 (d, 1H), 7.23 (dd, 1H), 6.83 (d, 1H), 5.70 (s,2H), 4.76 (t, 1H), 3.78-2.92 (m, 8H), 1.53 (s, 6H).

LC/MS (m/z) [M+1]⁺ 526.1 (calculated for C₂₆H₂₈ClN₅O₃S, 525.2).

Example 2305-({1-[2-Chloro-4-(1-methylethenyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3-(R)-(hydroxymethyl)piperazin-1-yl]-1,3-thiazol-4(5H)-one

5-({1-[2-Chloro-4-(1-methylethenyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3-(R)-(hydroxymethyl)piperazin-1-yl]-1,3-thiazol-4(5H)-onewas obtained as a side product during the deprotection of the Bocprotecting group of4-[5-{1-[2-Chloro-4-(1-hydroxy-1-methyl-ethyl)-benzyl]-1H-indazol-5-ylmethylene}-4-oxo-4,5-dihydro-thiazol-2-yl)-2-(R)-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester (example 229) following General Procedure H.

¹H NMR (400 MHz, CDCl₃) δ 8.15 (m, 1H), 7.94 (s, 1H), 7.92 (s, 1H), 7.53(dd, 1H), 7.49 (d, 1H), 7.44 (d, 1H), 7.23 (dd, 1H), 6.81 (d, 1H), 5.69(s, 2H), 5.34 (s, 1H), 5.10 (m, 1H) 4.76 (t, 1H), 3.77-2.92 (m, 8H),2.07 (s, 3H).

LC/MS (m/z) [M+1]⁺ 506.1 (calculated for C₂₆H₂₆ClN₅O₂S, 507.2).

Example 2315-({1-[2-Chloro-4-(1-hydroxy-1-methylethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[2-(R)-(hydroxymethyl)morpholin-4-yl]-1,3-thiazol-4(5H)-one

5-({1-[2-Chloro-4-(1-hydroxy-1-methylethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[2-(R)-(hydroxymethyl)morpholin-4-yl]-1,3-thiazol-4(5H)-onewas prepared from5-{1-[2-Chloro-4-(1-hydroxy-1-methyl-ethyl)-benzyl]-1H-indazol-5-ylmethylene}-2-ethylsulfanyl-thiazol-4-oneand (2R) Morpholin-2-yl-methanol following General Procedure C.

¹H NMR (400 MHz, CDCl₃) δ 8.12 (s, 1H), 7.91 (br s, 2H), 7.56 (d, 1H),7.49 (d, 1H), 7.41 (dd, 1H), 7.22 (dd, 1H), 6.81 (d, 1H), 5.66 (d, 2H),4.77 (t, 1H), 4.04 (d, 1H), 3.79-3.22 (m, 7H), 2.42 (br s, 1H), 1.52 (s,6H).

LC/MS (m/z) [M+1]⁺ 527.1 (calculated for C₂₆H₂₇ClN₄O₄S, 526.1).

Example 2325-({1-[2-Chloro-4-(1-hydroxy-1-methylethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(4-methylpiperazin-1-yl)-1,3-thiazol-4(5H)-one

5-({1-[2-Chloro-4-(1-hydroxy-1-methylethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(4-methylpiperazin-1-yl)-1,3-thiazol-4(5H)-onewas prepared from5-{1-[2-Chloro-4-(1-hydroxy-1-methyl-ethyl)benzyl]-1H-indazol-5-ylmethylene}-2-ethylsulfanyl-thiazol-4-oneand 1-Methyl-piperazine following General Procedure C.

¹H NMR (400 MHz, CDCl₃) δ 8.15 (s, 1H), 7.95 (s, 1H), 7.93 (s, 1H), 7.57(d, 1H), 7.5 (dd, 1H), 7.46 (d, 1H), 7.22 (dd, 1H), 6.82 (d, 1H), 5.69(s, 2H), 4.08 (t, 2H), 3.66 (t, 3H), 2.56 (m, 4H), 2.36 (s, 3H), 1.86(br s, 1H), 1.53 (s, 6H).

LC/MS (m/z) [M+1]⁺ 510.2 (calculated for C₂₆H₂₈ClN₅O₂S, 509.1).

Example 2335-({1-[2-Chloro-4-(1-hydroxy-1-methylethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(3,5-(cis)-dimethylpiperazin-1-yl)-1,3-thiazol-4(5H)-one

5-({1-[2-Chloro-4-(1-hydroxy-1-methylethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(3,5-(cis)-dimethylpiperazin-1-yl)-1,3-thiazol-4(5H)-onewas prepared from5-{1-[2-Chloro-4-(1-hydroxy-1-methyl-ethyl)-benzyl]-1H-indazol-5-ylmethylene}-2-ethylsulfanyl-thiazol-4-oneand 2,6-(cis)-Dimethyl-piperazine following General Procedure C.

¹H NMR (400 MHz, CDCl₃) δ 8.14 (s, 1H), 7.94 (s, 1H), 7.91 (s, 1H), 7.56(d, 1H), 7.53 (dd, 1H), 7.45 (d, 1H), 7.22 (dd, 1H), 6.82 (d, 1H), 5.68(s, 2H), 4.84 (d, 1H), 3.65 (d, 1H), 3.12-2.95 (m, 2H), 2.72 (t, 1H),1.67 (br s, 2H), 1.52 (s, 6H), 1.18 (d, 3H), 1.12 (d, 3H).

LC/MS (m/z) [M+1]⁺ 524.2 (calculated for C₂₇H₃₀ClN₅O₂S, 523.2).

Example 2345-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[2-(S)-(methoxymethyl)morpholin-4-yl]-1,3-thiazol-4(5H)-one

A. (2S)-2-Methoxymethyl-morpholine was prepared as described in J. Med.Chem. 1994, 37, 2791-2796.

B.5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[2-(S)-(methoxymethyl)morpholin-4-yl]-1,3-thiazol-4(5H)-onewas prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand (2S)-2-Methoxymethyl-morpholine following General Procedure C.

¹H NMR (400 MHz, CDCl₃) δ 8.23 (d, 1H), 8.00-7.96 (m, 3H), 7.64 (d, 1H),7.56 (m, 1H), 7.33 (d, 1H), 6.83 (d, 1H), 5.89 (s, 2H), 4.81 (dd, 1H),4.11 (dd, 1H), 3.81-3.24 (m, 11H).

LC/MS (m/z) [M+1]⁺ 585.2 (calculated for C₂₆H₂₂F₆N₄O₃S, 584.1).

Example 2355-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[2-(S)-(methoxymethyl)morpholin-4-yl]-1,3-thiazol-4(5H)-one

5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[2-(S)-(methoxymethyl)morpholin-4-yl]-1,3-thiazol-4(5H)-onewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand (2S)-2-Methoxymethyl-morpholine following General Procedure C.

¹H NMR (400 MHz, CDCl₃) δ 8.19 (d, 1H), 7.98-7.95 (m, 2H), 7.71 (s, 1H),7.54 (dd, 1H), 7.35-7.30 (m, 2H), 6.67 (d, 1H), 5.79 (s, 2H), 4.81 (dd,1H), 4.10 (dd, 1H), 3.79-3.23 (m, 11H).

LC/MS (m/z) [M+1]⁺ 551.2 (calculated for C₂₅H₂₂ClF₃N₄O₃S, 550.1).

Example 2365-({1-[4-Hydroxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[2(S)-(methoxymethyl)morpholin-4-yl]-1,3-thiazol-4(5H)-one

5-({1-[4-Hydroxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[2(S)-(methoxymethyl)morpholin-4-yl]-1,3-thiazol-4(5H)-onewas prepared from2-Ethylsulfanyl-5-[1-(4-hydroxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-oneand (2S)-2-Methoxymethyl-morpholine following General Procedure C.

¹H NMR (400 MHz, CDCl₃) δ 10.19 (s, 1H), 8.29 (d, 1H), 8.13 (s, 1H),7.80 (s, 1H), 7.73-7.66 (m, 2H), 7.12 (d, 1H), 6.92 (dd, 1H), 6.71 (dd,1H), 5.73 (s, 2H), 4.49 (dd, 1H), 4.98 (t, 1H), 3.80-3.16 (m, 11H).

LC/MS (m/z) [M+1]⁺ 533.2 (calculated for C₂₅H₂₃ClF₃N₄O₄S, 532.1).

Example 2375-({1-[4-Bromo-2-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[2-(R)-(hydroxymethyl)morpholin-4-yl]-1,3-thiazol-4(5H)-one

5-({1-[4-Bromo-2-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[2-(R)-(hydroxymethyl)morpholin-4-yl]-1,3-thiazol-4(5H)-onewas prepared from5-[1-(4-Bromo-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand (2R)-2-Methoxymethyl-morpholine following General Procedure C.

¹H NMR (400 MHz, CDCl₃) δ 8.19 (d, 1H), 7.97 (s, 1H), 7.94 (s, 1H), 7.86(d, 1H), 7.53 (d, 1H), 7.48 (dd, 1H), 7.31 (d, 1H), 6.59 (d, 1H), 5.76(s, 2H), 4.80 (t, 1H), 4.11 (dd, 1H), 3.85-3.25 (m, 7H).

LC/MS (m/z) [M+1]⁺ 581.3 (calculated for C₂₄H₂₀BrF₃N₄O₃S, 580.0).

Example 2385-({1-[2,4-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(3,5-(cis)-dimethylpiperazin-1-yl)-1,3-thiazol-4(5H)-one

5-({1-[2,4-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(3,5-(cis)-dimethylpiperazin-1-yl)-1,3-thiazol-4(5H)-onewas prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 2,6-(cis)-Dimethyl-piperazine following General Procedure C.

¹H NMR (400 MHz, CDCl₃) δ 8.23 (s, 1H), 7.98 (br s, 2H), 7.91 (s, 1H),7.63 (d, 1H), 7.55 (dd, 1H), 7.32 (d, 1H), 6.83 (d, 1H), 5.89 (s, 2H),4.84 (d, 1H), 3.63 (d, 1H), 3.12-2.95 (m, 2H), 2.81 (t, 1H), 2.10 (br s,1H), 1.21 (d, 3H), 1.15 (d, 3H).

LC/MS (m/z) [M+1]⁺ 568.2 (calculated for C₂₆H₂₃F₆N₅OS, 567.2).

Example 2395-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)-1,3-thiazol-4(5H)-one

To 4 mL of THF was added5-({1-[2,4-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(3,5-(cis)-dimethylpiperazin-1-yl)-1,3-thiazol-4(5H)-one(example 238, 45 mg), followed by 50 mg of 37% HCHO. The mixture wasstirred at room temperature for 20 min, and then 15 mg of NaBH₃CN wasadded. The reaction mixture was kept stirring for 3 h, concentrated invacuo and partitioned between CH₂Cl₂ and water. The combined organicextracts were washed with brine, dried, and evaporated. The residue waspurified by flash column chromatography on silica gel, eluting withMeOH/Dichloromethane (10/90) to afford the title product.

¹H NMR (400 MHz, CDCl₃) δ 8.24 (s, 1H), 7.99-7.97 (br s, 2H), 7.91 (s,1H), 7.63 (d, 1H), 7.55 (dd, 1H), 7.32 (d, 1H), 6.83 (d, 1H), 5.89 (s,2H), 4.81 (d, 1H), 3.64 (d, 1H), 3.14-2.95 (m, 3H), 2.85 (t, 1H), 2.47(s, 3H), 1.20 (d, 3H), 1.14 (d, 3H).

LC/MS (m/z) [M+1]⁺ 582.2 (calculated for C₂₇H₂₅F₆N₅OS, 581.2).

Example 240(2R,6S)-4-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-1,1,2,6-tetramethylpiperazin-1-iumchloride

To a solution of5-({1-[2,4-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(3,5-(cis)-dimethylpiperazin-1-yl)-1,3-thiazol-4(5H)-one(50 mg, 0.088 mmol) in DMF (2 mL) was added potassium carbonate (21.2mg, 0.15 mmol) and methyl iodide (30 mg, 0.21 mmol). After stirring forat room temperature for 15 h, the solid formed was collected byfiltration, dried, dissolved in MeOH/dichloromethane and precipitatedout with a 1.0M solution of HCl in diethyl ether to give the titlecompound as a solid.

¹H NMR (400 MHz, DMSO-d₆) δ 8.33 (s, 1H), 8.16 (s, 1H), 8.10 (s, 1H),7.96 (d, 1H), 7.85 (s, 1H), 7.81 (d, 1H), 7.70 (d, 1H), 6.94 (d, 1H),5.97 (s, 2H), 4.63 (d, 1H), 4.02-3.86 (m, 4H), 3.49-3.35 (m, 4h), 3.10(s, 3H), 2.91 (s, 3H), 2.48 (m, 6H)

LC/MS (m/z) M⁺ 596.2 (calculated for C₂₈H₂₈F₆N₆OS, 596.0).

Example 2415-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-((3R,5S)-3,5-dimethylpiperazin-1-yl)-1,3-thiazol-4(5H)-one

5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-((3R,5S)-3,5-dimethylpiperazin-1-yl)-1,3-thiazol-4(5H)-onewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand (2R,6S) 2,6-Dimethyl-piperazine following General Procedure C.

¹H NMR (400 MHz, CDCl₃) δ 8.19 (s, 1H), 7.97 (s, 1H), 7.93 (s, 1H), 7.71(d, 1H), 7.55 (d, 1H), 7.35-7.30 (m, 2H), 6.66 (d, 1H), 5.79 (s, 2H),4.85 (d, 1H), 3.64 (d, 1H), 3.05-2.95 (m, 3H), 2.75 (t, 1H), 1.80 (br s,1H), 1.19 (d, 3H), 1.14 (d, 3H).

LC/MS (m/z) [M+1]⁺ 568.2 (calculated for C₂₅H₂₃ClF₃N₅OS, 567.2).

Example 2425-({1-[4-(1-Hydroxy-1-methylethyl)-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(4-methylpiperazin-1-yl)-1,3-thiazol-4(5H)-one

A. 2-(4-Methyl-3-trifluoromethyl-phenyl)-propan-2-ol

To a solution of 4-Bromo-1-methyl-2-trifluoromethyl-benzene (3.4 g, 14.2mmol) in THF was added n-BuLi at −78° C. After the reaction mixture wasstirred at −78° C. for 30 minutes, dry acetone was slowly added. Theresulting content was maintained at −78° C. for 3 hours and slowlywarmed up to RT overnight. The reaction mixture was then partitionedbetween ethyl acetate and water. The ethyl acetate layer was then washedwith brine, dried over Na₂SO₄, filtered, and the solvent evaporated invacuo to yield a crude oil. The crude solid was purified via flashchromatography (15% EtOAc in n-hexane) yielded the title compound as anoil (2.7 g, 86%).

¹H NMR (400 MHz, CDCl₃) δ 7.73 (d, 1H), 7.53 (dd, 1H), 7.25 (d, 1H),2.47 (q, 3H), 1.58 (s, 6H).

B. 2-(4-Bromomethyl-3-trifluoromethyl-phenyl)-propan-2-ol was preparedfollowing procedure described for example 9-A.

¹H NMR (400 MHz, CDCl₃) δ 7.78 (d, 1H), 7.65 (dd, 1H), 7.55 (d, 1H),4.63 (s, 2H), 1.59 (s, 6H).

C.5-({1-[4-(1-Hydroxy-1-methylethyl)-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(4-methylpiperazin-1-yl)-1,3-thiazol-4(5H)-onewas prepared from2-Ethylsulfanyl-5-{1-[4-(1-hydroxy-1-methyl-ethyl)-2-trifluoromethyl-benzyl]-1H-indazol-5-ylmethylene}-thiazol-4-oneand 1-Methyl-piperazine following General Procedure C.

¹H NMR (400 MHz, CDCl₃) δ 8.18 (s, 1H), 7.98 (s, 1H), 7.93 (s, 1H), 7.87(d, 1H), 7.53 (dd, 1H), 7.45 (dd, 1H), 7.34 (d, 1H), 6.66 (d, 1H), 5.82(s, 2H), 4.10 (t, 2H), 3.65 (t, 3H), 2.57 (m, 4H), 2.37 (s, 3H), 1.55(s, 6H).

LC/MS (m/z) [M+1]⁺ 544.2 (calculated for C₂₇H₂₈F₃N₅O₂S, 543.2).

Example 2432-((3R,5S)-3,5-Dimethylpiperazin-1-yl)-5-({1-[4-(1-hydroxy-1-methylethyl)-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazol-4(5H)-one

2-((3R,5S)-3,5-Dimethylpiperazin-1-yl)-5-({1-[4-(1-hydroxy-1-methylethyl)-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazol-4(5H)-onewas prepared from2-Ethylsulfanyl-5-{1-[4-(1-hydroxy-1-methyl-ethyl)-2-trifluoromethyl-benzyl]-1H-indazol-5-ylmethylene}-thiazol-4-oneand (2R,6S) 2,6-Dimethyl-piperazine following General Procedure C.

¹H NMR (400 MHz, CDCl₃) δ 8.16 (s, 1H), 7.94 (s, 1H), 7.89 (s, 1H), 7.85(s, 1H), 7.50 (d, 1H), 7.42 (d, 1H), 7.31 (d, 1H), 6.63 (d, 1H), 5.79(s, 2H), 4.82 (d, 1H), 3.62 (d, 1H), 3.01-2.91 (m, 2H), 2.70 (t, 1H),2.15 (br s, 1H), 1.53 (s, 6H), 1.17 (d, 3H), 1.10 (d, 3H).

LC/MS (m/z) [M+1]⁺ 558.3 (calculated for C₂₈H₃₀F₃N₅O₂S, 557.2).

Example 2445-({1-[4-(1-Hydroxy-1-methylethyl)-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[2-(S)-(hydroxymethyl)morpholin-4-yl]-1,3-thiazol-4(5H)-one

5-({1-[4-(1-Hydroxy-1-methylethyl)-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[2-(S)-(hydroxymethyl)morpholin-4-yl]-1,3-thiazol-4(5H)-onewas prepared from2-Ethylsulfanyl-5-{1-[4-(1-hydroxy-1-methyl-ethyl)-2-trifluoromethyl-benzyl]-1H-indazol-5-ylmethylene}-thiazol-4-oneand (2S) Morpholin-2-yl-methanol following General Procedure C.

¹H NMR (400 MHz, CDCl₃) δ 8.15 (s, 1H), 7.92 (s, 1H), 7.90 (s, 1H), 7.87(s, 1H), 7.48-7.44 (m, 2H), 7.29 (dd, 1H), 6.64 (d, 1H), 5.79-5.77 (2H),4.75 (dd, 1H), 4.08 (dd, 1H), 3.79-2.75 (m, 8H), 1.54 (s, 6H).

LC/MS (m/z) [M+1]⁺ 561.3 (calculated for C₂₇H₂₇ClF₃N₄O₄S, 560.2).

Example 2454-[(5Z)-5-({1-[4-(1-Hydroxy-1-methylethyl)-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]piperazine-1-carboxylicacid

4-[(5Z)-5-({1-[4-(1-Hydroxy-1-methylethyl)-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]piperazine-1-carboxylicacid was prepared from2-Ethylsulfanyl-5-{1-[4-(1-hydroxy-1-methyl-ethyl)-2-trifluoromethyl-benzyl]-1H-indazol-5-ylmethylene}-thiazol-4-oneand Piperidine-4-carboxylic acid following General Procedure C.

¹H NMR (400 MHz, CDCl₃) δ 8.19 (s, 1H), 7.96 (s, 1H), 7.94 (s, 1H), 7.87(s, 1H), 7.52 (d, 1H), 7.45 (dd, 1H), 7.33 (d, 1H), 6.65 (d, 1H), 5.81(s, 2H), 4.63 (dd, 1H), 3.87 (dd, 1H), 3.59-3.44 (m, 2H), 2.76 (m, 1H),2.18-2.07 (m, 2H), 1.99-1.87 (m, 2H), 1.55 (s, 6H).

LC/MS (m/z) [M+1]⁺ 561.3 (calculated for C₂₇H₂₇ClF₃N₄O₄S, 560.2).

Example 2465-({1-[4-(1-Hydroxy-1-methylethyl)-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3-(R)-(hydroxymethyl)piperazin-1-yl]-1,3-thiazol-4(5H)-one

A.(2R)-2-Hydroxymethyl-4-(5-{1-[4-(1-hydroxy-1-methyl-ethyl)-2-trifluoromethyl-benzyl]-1H-indazol-5-ylmethylene}-4-oxo-4,5-dihydro-thiazol-2-yl)-piperazine-1-carboxylic acidtert-butyl ester was prepared from2-Ethylsulfanyl-5-{1-[4-(1-hydroxy-1-methyl-ethyl)-2-trifluoromethyl-benzyl]-1H-indazol-5-ylmethylene}-thiazol-4-oneand (2R) 2-Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl esterfollowing General Procedure C.

LC/MS (m/z) [M+1]⁺ 660.3 (calculated for C₃₂H₃₆F₃N₅O₅S, 659.24).

B.5-({1-[4-(1-Hydroxy-1-methylethyl)-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3-(R)-(hydroxymethyl)piperazin-1-yl]-1,3-thiazol-4(5H)-onewas prepared from (2R)2-Hydroxymethyl-4-(5-{1-[4-(1-hydroxy-1-methyl-ethyl)-2-trifluoromethyl-benzyl]-1H-indazol-5-ylmethylene}-4-oxo-4,5-dihydro-thiazol-2-yl)-piperazine-1-carboxylicacid tert-butyl ester following General Procedure H.

¹H NMR (400 MHz, CD₃OD) δ 8.23 (s, 1H), 8.11 (s, 1H), 7.92 (br s, 2H),7.64 (d, 1H), 7.52-7.50 (d, 2H), 6.64 (d, 1H), 5.85 (s, 2H), 4.14 (d,1H), 3.92-3.34 (m, 8H), 1.49 (s, 6H).

LC/MS (m/z) [M+1]⁺ 560.3 (calculated for C₂₇H₂₇ClF₃N₄O₄S, 559.2).

Example 2472-[3-(R)—(Hydroxymethyl)piperazin-1-yl]-5-({1-[4-(1-methylethenyl)-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazol-4(5H)-one

2-[3-(R)—(Hydroxymethyl)piperazin-1-yl]-5-({1-[4-(1-methylethenyl)-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazol-4(5H)-onewas obtained as a side product during the deprotection of the Bocprotecting group of (2R)2-Hydroxymethyl-4-(5-{1-[4-(1-hydroxy-1-methyl-ethyl)-2-trifluoromethyl-benzyl]-1H-indazol-5-ylmethylene}-4-oxo-4,5-dihydro-thiazol-2-yl)-piperazine-1-carboxylicacid tert-butyl ester (example 246) following General Procedure H.

¹H NMR (400 MHz, CDCl₃) δ 8.18 (m, 1H), 7.96 (s, 1H), 7.92 (s, 1H), 7.78(s, 1H), 7.52 (dd, 1H), 7.42 (d, 1H), 7.32 (dd, 1H), 6.66 (d, 1H),5.83-5.81 (2H), 5.38 (s, 1H), 5.15 (s, 1H) 4.49-4.72 (m, 1H), 3.80-2.91(m, 9H), 2.11 (s, 3H).

LC/MS (m/z) [M+1]⁺ 542.3 (calculated for C₂₆H₂₆ClN₅O₂S, 541.2).

Example 2482-[3-(R)—(Hydroxymethyl)piperazin-1-yl]-5-({1-[4-methoxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazol-4(5H)-one

A. (2R)2-Hydroxymethyl-4-{5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazine-1-carboxylicacid tert-butyl ester was prepared from2-Ethylsulfanyl-5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-oneand (2R) 2-Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl esterfollowing General Procedure C.

LC/MS (m/z) [M+1]⁺ 632.3 (calculated for C₃₀H₃₂F₃N₆O₆S, 631.21).

B.2-[3-(R)—(Hydroxymethyl)piperazin-1-yl]-5-({1-[4-methoxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazol-4(5H)-onewas prepared from (2R)2-Hydroxymethyl-4-{5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazine-1-carboxylicacid tert-butyl ester following General Procedure H.

¹H NMR (400 MHz, DMSO-d₆) δ 8.15 (s, 1H), 7.94-7.83 (m, 2H), 7.47 (d,1H), 7.32-7.21 (m, 2H), 6.87 (d, 1H), 6.69 (d, 1H), 5.72 (s, 2H), 4.77(d, 1H), 3.85-2.92 (m, 13H).

LC/MS (m/z) [M+1]⁺ 532.3 (calculated for C₂₆H₂₄F₃N₆O₃S, 531.2).

Example 2492-[(2R)-2-(Hydroxymethyl)morpholin-4-yl]-5-({1-[4-hydroxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazol-4(5H)-one

2-[(2R)-2-(Hydroxymethyl)morpholin-4-yl]-5-({1-[4-hydroxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazol-4(5H)-onewas prepared from2-Ethylsulfanyl-5-[1-(4-hydroxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-oneand (2R) Morpholin-2-yl-methanol following General Procedure C.

¹H NMR (400 MHz, DMSO-d₆) δ 10.17 (s, 1H), 8.29 (s, 1H), 8.12 (s, 1H),7.81 (s, 1H), 7.83-7.66 (m, 2H), 7.12 (d, 1H), 6.92 (dd, 1H), 6.71 (d,1H), 5.73 (s, 2H), 5.00-4.94 (m, 1H), 4.52 (dd, 1H), 4.02-3.13 (m, 7H).

LC/MS (m/z) [M+1]⁺ 519.1 (calculated for C₂₄H₂₁F₃N₄O₄S, 518.1).

Example 2502-[(3R)-3-(Hydroxymethyl)piperazin-1-yl]-5-({1-[4-hydroxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazol-4(5H)-one

A. (2R)2-Hydroxymethyl-4-{5-[1-(4-hydroxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazine-1-carboxylicacid tert-butyl ester was prepared from2-Ethylsulfanyl-5-[1-(4-hydroxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-oneand (2R) 2-Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl esterfollowing General Procedure C.

LC/MS (m/z) [M+1]⁺ 618.3 (calculated for C₃₀H₃₂F₃N₅O₅S, 617.19).

B.2-[(3R)-3-(Hydroxymethyl)piperazin-1-yl]-5-({1-[4-hydroxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazol-4(5H)-onewas prepared from (2R)2-Hydroxymethyl-4-{5-[1-(4-hydroxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazine-1-carboxylicacid tert-butyl ester following General Procedure H.

¹H NMR (400 MHz, CD₃OD) δ 8.20 (s, 1H), 8.07 (s, 1H), 7.86 (s, 1H), 7.60(d, 1H), 7.46 (d, 1H), 7.06 (d, 1H), 6.73 (dd, 1H), 6.55 (d, 1H), 5.70(s, 2H), 4.74-4.56 (m, 2H), 3.95-3.84 (m, 1H), 3.63-3.45 (m, 2H),3.25-2.84 (m, 4H).

LC/MS (m/z) [M+1]⁺ 518.2 (calculated for C₂₄H₂₂F₃N₅O₃S, 517.1).

Example 2512-[(2S)-2-(Hydroxymethyl)morpholin-4-yl]-5-({1-[4-hydroxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazol-4(5H)-one

2-[(2S)-2-(Hydroxymethyl)morpholin-4-yl]-5-({1-[4-hydroxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazol-4(5H)-onewas prepared from2-Ethylsulfanyl-5-[1-(4-hydroxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-oneand (2S) Morpholin-2-yl-methanol following General Procedure C.

¹H NMR (400 MHz, CD₃OD) δ 8.20 (s, 1H), 8.08 (s, 1H), 7.87 (s, 1H), 7.62(d, 1H), 7.49 (d, 1H), 7.14 (d, 1H), 6.82 (dd, 1H), 6.60 (d, 1H), 5.74(s, 2H), 4.64 (dd, 1H), 4.14-3.39 (m, 8H).

LC/MS (m/z) [M+1]⁺ 519.2 (calculated for C₂₄H₂₁F₃N₄O₄S, 518.1).

Example 2525-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[(3R)-3R)-3-(dimethylamino)pyrrolidin-1-yl]-1,3-thiazol-4(5H)-one

5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-1,3-thiazol-4(5H)-onewas prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand (3R) Dimethyl-pyrrolidin-3-yl-amine following General Procedure C.

¹H NMR (400 MHz, CDCl₃) δ 8.21 (s, 1H), 7.97 (br s, 2H), 7.90 (s, 1H),7.61 (d, 1H), 7.54 (dd, 1H), 7.30 (d, 1H), 6.80 (d, 1H), 5.87 (s, 2H),4.19-4.09 (m, 1H), 3.81-3.42 (m, 3H), 3.00-2.82 (m, 1H), 2.31 (s, 3H),2.29 (s, 3H), 2.12-1.81 (m, 2H).

LC/MS (m/z) [M+1]⁺ 568.2 (calculated for C₂₆H₂₃F₆N₅OS, 567.2).

Example 2535-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[(2R)-2-(hydroxymethyl)-4-methylpiperazin-1-yl]-1,3-thiazol-4(5H)-one

5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[(2R)-2-(hydroxymethyl)-4-methylpiperazin-1-yl]-1,3-thiazol-4(5H)-onewas prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand (2R) (4-Methyl-piperazin-2-yl)-methanol following General ProcedureC.

¹H NMR (400 MHz, CDCl₃) δ 8.19 (m, 1H), 7.98-7.90 (m, 3H), 7.64-7.50 (m,2H), 7.32-7.26 (m, 1H), 6.80-6.79 (m, 1H), 5.88-5.85 (m, 2H), 4.95-4.80(m, 1H), 4.23-3.62 (m, 4H), 3.11-2.90 (m, 2H), 2.45-2.17 (m, 5H).

LC/MS (m/z) [M+1]⁺ 584.2 (calculated for C₂₆H₂₃F₆N₅O₂S, 583.2).

Example 2545-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[(2R)-2-(hydroxymethyl)-4-methylpiperazin-1-yl]-1,3-thiazol-4(5H)-one

5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[(2R)-2-(hydroxymethyl)-4-methylpiperazin-1-yl]-1,3-thiazol-4(5H)-onewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand (2R) (4-Methyl-piperazin-2-yl)-methanol following General ProcedureC.

¹H NMR (400 MHz, CDCl₃) δ 8.18 (m, 1H), 7.98-7.91 (m, 2H), 7.71-7.50 (m,2H), 7.35-7.29 (m, 2H), 6.68-6.64 (m, 1H), 5.79-5.77 (m, 2H), 4.97-4.81(m, 1H), 4.20-3.66 (m, 4H), 3.14-2.91 (m, 2H), 2.48-2.19 (m, 5H).

LC/MS (m/z) [M+1]⁺ 550.1 (calculated for C₂₅H₂₃ClF₃N₅O₂S, 549.1).

Example 2555-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(2S)-2-ethylpiperazin-1-yl)-1,3-thiazol-4(5H)-one

A.4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-3-ethyl-piperazine-1-carboxylicacid tert-butyl ester was prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand (3S)-3-Ethyl-piperazine-1-carboxylic acid tert-butyl ester followingGeneral Procedure C.

LC/MS (m/z) [M+1]⁺ 634.2 (calculated for C₃₀H₃₁ClF₃N₅O₃S, 633.18).

B.5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-((2S)-2-ethylpiperazin-1-yl)-1,3-thiazol-4(5H)-one was prepared from4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-3-ethyl-piperazine-1-carboxylicacid tert-butyl ester following General Procedure H.

¹H NMR (400 MHz, CDCl₃) δ 8.22-8.20 (m, 1H), 7.98-7.93 (m, 2H),7.71-7.55 (m, 2H), 7.36-7.31 (m, 2H), 6.66 (d, 1H), 5.80 (s, 2H),4.93-4.77 (m, 1H), 3.70-3.58 (m, 1H), 3.38-2.83 (m, 5H), 2.13-1.77 (m,2H), 1.05-0.95 (m, 3H).

LC/MS (m/z) [M+1]⁺ 534.1 (calculated for C₂₅H₂₃ClF₃N₅OS, 533.1).

Example 2565-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(2S)-2-ethyl-4-methylpiperazin-1-yl)-1,3-thiazol-4(5H)-one

5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(2S)-2-ethyl-4-methylpiperazin-1-yl)-1,3-thiazol-4(5H)-onewas prepared from5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(2S)-2-ethylpiperazin-1-yl)-1,3-thiazol-4(5H)-oneand formaldehyde following procedure used as in example 195.

¹H NMR (400 MHz, CDCl₃) δ 8.20-8.18 (m, 1H), 7.97-7.92 (m, 2H),7.71-7.54 (m, 2H), 7.35-7.30 (m, 2H), 6.66 (d, 1H), 5.79 (s, 2H),4.93-4.72 (m, 2H), 3.75-2.87 (m, 5H), 2.33 (s, 3H), 2.09-1.88 (m, 2H),1.02-0.94 (m, 3H).

LC/MS (m/z) [M+1]⁺ 548.2 (calculated for C₂₆H₂₅ClF₃N₅OS, 547.1).

Example 2572-[(2R,4R)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl]-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazol-4(5H)-one

A.(1-{(3R,5R)-5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-5-hydroxymethyl-pyrrolidin-3-yl)-carbamicacid tert-butyl ester was prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand (3R,5R) (5-Hydroxymethyl-pyrrolidin-3-yl)-carbamic acid tert-butylester following General Procedure C.

LC/MS (m/z) [M+1]⁺ 636.2 (calculated for C₂₉H₂₉ClF₃N₅O₄S, 635.16).

B.2-[(2R,4R)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl]-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazol-4(5H)-onewas prepared from(1-{(3R,5R)-5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-5-hydroxymethyl-pyrrolidin-3-yl)-carbamicacid tert-butyl ester following General Procedure H.

¹H NMR (400 MHz, CDCl₃) δ 8.18-8.16 (m, 1H), 7.94-7.90 (m, 2H), 7.73 (d,1H), 7.51 (d, 1H), 7.34-7.27 (m, 2H), 6.65 (d, 1H), 5.77 (m, 2H),4.64-3.46 (m, 8H), 2.65-2.55 (m, 1H), 1.97-1.83 (m, 2H).

LC/MS (m/z) [M+1]⁺ 536.2 (calculated for C₂₄H₂₁ClF₃N₅O₂S, 535.1).

Example 2582-[(2R,4R)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl]-5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazol-4(5H)-one

A.(1-{(3R,5R)-5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-5-hydroxymethyl-pyrrolidin-3-yl)-carbamicacid tert-butyl ester was prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand (3R,5R) (5-Hydroxymethyl-pyrrolidin-3-yl)-carbamic acid tert-butylester following General Procedure C.

LC/MS (m/z) [M+1]⁺ 670.3 (calculated for C₃₀H₂₉F₆N₅O₄S, 669.18).

B.2-[(2R,4R)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl]-5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazol-4(5H)-onewas prepared from(1-{(3R,5R)-5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-5-hydroxymethyl-pyrrolidin-3-yl)-carbamicacid tert-butyl ester following General Procedure H.

¹H NMR (400 MHz, CDCl₃) δ 8.22-8.20 (m, 1H), 7.98-7.92 (m, 3H), 7.63 (d,1H), 7.54 (d, 1H), 7.31 (d, 1H), 6.81 (d, 1H), 5.87 (s, 2H), 4.66-3.46(m, 8H), 2.66-2.54 (m, 1H), 1.98-1.82 (m, 2H).

LC/MS (m/z) [M+1]⁺ 570.1 (calculated for C₂₅H₂₁F₆N₅O₂S, 569.1).

Example 259N-{1-[(3R,5R)-5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-5-(hydroxymethyl)pyrrolidin-3-yl}acetamide

N-{(3R,5R)-1-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-5-(hydroxymethyl)pyrrolidin-3-yl}acetamidewas prepared from2-[(2R,4R)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl]-5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazol-4(5H)-one(example 258) and acetic anhydride.

¹H NMR (400 MHz, CDCl₃) δ 8.13-8.11 (m, 1H), 7.97 (s, 1H), 7.91 (s, 1H),7.69 (s, 1H), 7.62-7.57 (m, 1H), 7.28 (d, 1H), 6.98 (d, 1H), 6.71 (d,1H), 5.71-5.60 (m, 3H), 4.91-4.79 (m, 2H), 4.50 (d, 1H), 3.97 (dd, 1H),3.72-3.61 (m, 2H), 2.73-2.64 (m, 1H), 2.10-2.00 (m, 4H).

LC/MS (m/z) [M+1]⁺ 612.2 (calculated for C₂₇H₂₃F₆N₅O₃S, 611.1).

Example 260N-{(3R,5R)-1-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-5-(hydroxymethyl)pyrrolidin-3-yl}cyclopropanecarboxamide

N-{(3R,5R)-1-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-5-(hydroxymethyl)pyrrolidin-3-yl}cyclopropanecarboxamidewas prepared from2-[(2R,4R)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl]-5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazol-4(5H)-one(example 258) and Cyclopropylcarbonyl chloride.

¹H NMR (400 MHz, CDCl₃) δ 8.28-8.25 (m, 1H), 7.96 (s, 1H), 7.91 (s, 1H),7.68 (s, 1H), 7.61-7.57 (m, 1H), 7.27 (d, 1H), 6.98 (d, 1H), 6.70 (d,1H), 5.87-5.64 (m, 3H), 4.86 (br s, 2H), 4.50 (d, 1H), 3.97 (dd, 1H),3.71-3.63 (m, 2H), 2.75-2.62 (m, 1H), 2.20-1.86 (m, 2H), 1.47 (br s,1H), 1.01 (m, 2H), 0.80 (m, 2H).

LC/MS (m/z) [M+1]⁺ 638.2 (calculated for C₂₉H₂₅F₆N₅O₃S, 637.2).

Example 261N-{(3R,5R)-1-[5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-5-(hydroxymethyl)pyrrolidin-3-yl}acetamide

N-{(3R,5R)-1-[5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-5-(hydroxymethyl)pyrrolidin-3-yl}acetamidewas prepared from2-[(2R,4R)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl]-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazol-4(5H)-one(example 257) and acetic anhydride.

¹H NMR (400 MHz, CDCl₃) δ 8.08-8.06 (m, 1H), 7.90 (s, 1H), 7.70 (s, 1H),7.61 (s, 1H), 7.31-7.24 (m, 2H), 6.97 (d, 1H), 6.55 (d, 1H), 5.67-5.56(m, 2H), 4.90-4.80 (m, 2H), 4.50 (d, 1H), 3.97 (dd, 1H), 3.71-3.62 (m,2H), 2.72-2.64 (m, 1H), 2.09-2.00 (m, 5H).

LC/MS (m/z) [M+1]⁺ 578.2 (calculated for C₂₆H₂₃ClF₃N₅O₃S, 577.1).

Example 262N-{(2R,4R)-1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-{2-(hydroxymethyl)-4-[(1-methylethyl)amino]pyrrolidin-1-yl}-1,3-thiazol-4(5H)-one

To a solution of CH₂Cl₂ (1 mL) and acetic acid (50 μL) was added2-[(2R,4R)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl]-5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazol-4(5H)-one(example 258, 35 mg, 0.061 mmol), followed by acetone (20 mg, 0.34mmol). After stirring the mixture at room temperature for 20 min, it wasadded NaBH(OAc)₃ (29 mg, 0.14 mmol). The reaction mixture was keptstirring for 48 h and partitioned between CH₂Cl₂ and water. The combinedorganic extracts were washed with brine, dried, and evaporated. Theresidue was purified by reverse phase semi-preparative HPLC to affordthe title product.

¹H NMR (400 MHz, CDCl₃) δ 8.20-8.18 (m, 1H), 7.98-7.90 (m, 3H), 7.63 (d,1H), 7.53 (d, 1H), 7.31-7.28 (m, 1H), 6.81 (d, 1H), 5.87-5.85 (m, 2H),4.63-3.52 (m, 6H), 2.92 (m, 1H), 2.61-2.50 (m, 1H), 2.07-1.89 (m, 1H),1.18-1.14 (m, 6H).

LC/MS (m/z) [M+1]⁺ 612.5 (calculated for C₂₈H₂₇F₆N₅O₂S, 611.2).

Example 263N-{(2R,4R)-1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-{2-(hydroxymethyl)-4-[(1-methylethyl)amino]pyrrolidin-1-yl}-1,3-thiazol-4(5H)-one

N-{(2R,4R)-1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-{2-(hydroxymethyl)-4-[(1-methylethyl)amino]pyrrolidin-1-yl}-1,3-thiazol-4(5H)-onewas prepared from2-[(2R,4R)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl]-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazol-4(5H)-one(example 257) and acetone following procedure used in example 262.

¹H NMR (400 MHz, CDCl₃) δ 8.16-8.14 (m, 1H), 7.92-7.87 (m, 2H), 7.71 (d,1H), 7.50 (dd, 1H), 7.33 (dd, 1H), 7.29-7.26 (m, 1H), 6.64 (d, 1H),5.77-5.86 (m, 2H), 4.62-3.52 (m, 6H), 2.92 (m, 1H), 2.62-2.50 (m, 1H),2.07-1.89 (m, 1H), 1.17-1.14 (m, 6H).

LC/MS (m/z) [M+1]⁺ 578.4 (calculated for C₂₇H₂₇ClF₃N₅O₂S, 577.2).

Example 264N-2-{(3S)-1-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]pyrrolidin-3-yl}alaninamide

A. (3S)-3-(1-Carbamoyl-ethylamino)-pyrrolidine-1-carboxylic acidtert-butyl ester

To a solution of MeCN (3 mL) was added 3-Amino-pyrrolidine-1-carboxylicacid tert-butyl ester (0.186 g, 1 mmol), 2-Bromo-propionamide (0.15 g, 1mmol) and potassium carbonate (0.153 g, 1.1 mmol). The resulting mixturewas heated at 80° C. overnight and partitioned between dichloromethaneand water. The combined organic extracts were washed with brine, dried,and evaporated. The residue was purified by flash column chromatographyon silica gel, eluting with MeOH/CH₂Cl₂ (20/80) to afford the titleproduct.

¹H NMR (400 MHz, CDCl₃) δ 7.02 (br s, 1H), 6.27 (br s, 1H), 3.52-2.96(m, 6H), 2.08-1.53 (m, 3H), 1.40-1.25 (m, 12H).

B. (2S)-2-(Pyrrolidin-3-ylamino)-propionamide was prepared from(3S)-3-(1-Carbamoyl-ethylamino)-pyrrolidine-1-carboxylic acid tert-butylester following General Procedure H and used directly into the nextstep.

C.N-2-{(3S)-1-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]pyrrolidin-3-yl}alaninamidewas prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand (2S)-2-(Pyrrolidin-3-ylamino)-propionamide following GeneralProcedure C.

¹H NMR (400 MHz, CDCl₃) δ 8.18-8.10 (1H), 7.97 (br s, 1H), 7.91-7.85(2H), 7.62-7.60 (1H), 7.51-7.47 (1H), 7.26-7.21 (1H), 7.06-6.94 (1H),6.81-6.77 (1H), 5.93-5.66 (3H), 4.07-3.08 (6H), 2.39-1.83 (3H),1.53-1.36 (3H).

LC/MS (m/z) [M+1]⁺ 611.5 (calculated for C₂₇H₂₄F₆N₆O₂S, 610.2).

Example 265N-2-{(3S)-1-[5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]pyrrolidin-3-yl}alaninamide

N-2-{(3S)-1-[5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]pyrrolidin-3-yl}alaninamidewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand (2S)-2-(Pyrrolidin-3-ylamino)-propionamide following GeneralProcedure C.

¹H NMR (400 MHz, CDCl₃) δ 8.14-8.06 (1H), 7.89-7.83 (2H), 7.70 (br 1H),7.48-7.42 (1H), 7.36-7.18 (2H), 7.15-6.89 (1H), 6.66-6.81 (1H), 6.02,6.08 (1H), 5.75-5.69 (2H), 4.08-3.07 (6H), 2.39-1.96 (3H), 1.56-1.37(3H).

LC/MS (m/z) [M+1]⁺ 577.5 (calculated for C₂₆H₂₄ClF₃N₆O₂S, 576.1).

Example 2665-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-{(3S)-3-[(2,2-difluoroethyl)amino]piperidin-1-yl}-1,3-thiazol-4(5H)-one

To a solution of DMF (1 mL) was added2-(3-(S)-Amino-piperidin-1-yl)-5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one(0.03 g, 0.05 mmol), Trifluoro-methanesulfonic acid 2,2-difluoro-ethylester (0.02 g, 0.09 mmol) and potassium carbonate (0.014 g, 0.1 mmol).The resulting mixture was heated at 70° C. overnight and partitionedbetween dichloromethane and water. The combined organic extracts werewashed with brine, dried, and evaporated. The residue was purified byflash column chromatography on silica gel, eluting with MeOH/CH₂Cl₂(7/93) to afford the title product.

¹H NMR (400 MHz, CDCl₃) δ 8.23-8.21 (m, 1H), 7.98 (br s, 2H), 7.93 (s,1H), 7.63 (d, 1H), 7.56 (d, 1H), 6.82 (d, 1H), 6.00-5.68 (m, 3H),4.52-4.44 (m, 1H), 3.84-2.84 (m, 6H), 2.14-1.46 (m, 4H).

LC/MS (m/z) [M+1]⁺ 618.2 (calculated for C₂₇H₂₃F₈N₅OS, 617.2).

Example 2675-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-{3-[(2-hydroxyethyl)amino]piperidin-1-yl}-1,3-thiazol-4(5H)-one

A. 3-(2-Hydroxy-ethylamino)-piperidine-1-carboxylic acid tert-butylester

To a solution of 3-Oxo-piperidine-1-carboxylic acid tert-butyl ester(0.2 g, 1 mmol) in dichloromethane (5 mL) was added 2-Amino ethanol(0.073 mg, 1.2 mmol) and NaBH(OAc)₃ (0.3 g, 1.4 mmol). The resultingmixture was stirred at room temperature overnight and partitionedbetween dichloromethane and water. The combined organic extracts werewashed with brine, dried, and evaporated. The residue was directly usedinto the next step without further purification.

LC/MS (m/z) [M]⁺ 245.3 (calculated for C₁₂H₂₄N₂O₃, 244.2).

B. 2-(Piperidin-3-ylamino)-ethanol was prepared from3-(2-Hydroxy-ethylamino)-piperidine-1-carboxylic acid tert-butyl esterfollowing General Procedure H.

C.5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-{(3S)-3-[(2-hydroxyethyl)amino]piperidin-1-yl}-1,3-thiazol-4(5H)-onewas prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 2-(Piperidin-3-ylamino)-ethanol following General Procedure C.

¹H NMR (400 MHz, DMSO-d₆) δ 8.34-8.32 (1H), 8.15-8.10 (m, 2H), 7.96 (d,1H), 7.82-7.78 (m, 2H), 7.69 (d, 1H), 6.91 (d, 1H), 6.00 (s, 2H),5.37-5.29 (m, 1H), 4.56 (d, 1H), 4.34-4.15 (m, 1H), 3.80-3.36 (m, 4H),3.16-3.00 (m, 2H), 2.21-1.56 (m, 4H).

LC/MS (m/z) [M+1]⁺ 598.3 (calculated for C₂₇H₂₅F₆N₅O₂S, 597.2).

Example 2681-[5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-4-hydroxypiperidine-4-carboxylicacid

1-[5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-4-hydroxypiperidine-4-carboxylicacid was prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 4-Hydroxy-piperidine-4-carboxylic acid following General ProcedureC.

¹H NMR (400 MHz, DMSO-d₆) δ 8.30 (s, 1H), 8.12 (s, 1H), 7.96 (s, 1H),7.86 (d, 1H), 7.77 (s, 1H), 7.74 (d, 1H), 7.67 (dd, 1H), 7.63 (dd, 1H),7.35 (d, 1H), 7.22 (d, 1H), 6.75 (d, 1H), 5.84 (s, 2H), 4.48 (d, 1H),3.78-3.63 (m, 2H), 3.44-3.30 (m, 1H), 2.04-1.91 (m, 2H), 21.71-1.60 (m,2H).

LC/MS (m/z) [M]⁺ 564.3 (calculated for C₂₅H₂₀ClF₃N₄O₄S, 564.1).

Example 2691-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-4-hydroxypiperidine-4-carboxylicacid

1-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-4-hydroxypiperidine-4-carboxylicacid was prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 4-Hydroxy-piperidine-4-carboxylic acid following General ProcedureC.

¹H NMR (400 MHz, DMSO-d₆) δ 8.33 (s, 1H), 8.13 (s, 1H), 8.10 (s, 1H),7.95 (d, 1H), 7.79-7.76 (m, 2H), 7.69 (d, 1H), 7.35 (d, 1H), 7.35 (d,1H), 7.22 (d, 1H), 6.90 (d, 1H), 5.96 (s, 2H), 4.48 (d, 1H), 3.78-3.62(m, 2H), 3.49-3.24 (m, 1H), 2.05-1.91 (m, 2H), 21.71-1.61 (m, 2H).

LC/MS (m/z) [M]⁺ 598.1 (calculated for C₂₆H₂₀F₆N₄O₄S, 598.1).

Example 2705-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3-(methylamino)azetidin-1-yl]-1,3-thiazol-4(5H)-one

A.5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3-(methylamino)azetidin-1-yl]-1,3-thiazol-4(5H)-onewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand Azetidin-3-yl-methyl-amine following General Procedure C.

¹H NMR (400 MHz, CDCl₃) δ 8.13 (s, 1H), 7.90 (s, 1H), 7.88 (s, 1H), 7.71(d, 1H), 7.48 (dd, 1H), 7.32 (dd, 1H), 7.27 (d, 1H), 6.64 (d, 1H), 5.76(s, 2H), 4.59 (dd, 1H), 4.43 (dd, 1H), 4.18 (dd, 1H), 4.04 (dd, 1H),3.94-3.88 (m, 1H), 2.47 (s, 3H).

LC/MS (m/z) [M+1]⁺ 506.1 (calculated for C₂₃H₁₉ClF₃N₅OS, 505.1).

Example 2714-[5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-N-methoxypiperazine-2-carboxamide

A. 2-Methoxycarbamoyl-piperazine-1,4-dicarboxylic acid 4-benzyl ester1-tert-butyl ester

To a solution of piperazine-1,2,4-tricarboxylic acid 4-benzyl ester1-tert-butyl ester (0.364 g, 1 mmol) in dichloromethane (3 mL) was addedO-Methyl Hydroxylamine HCl (95 mg, 1.13 mmol), EDC HCl (0.3 g, 1.57mmol) and DIEA (0.28 g, 2.17 mmol). The resulting mixture was stirred atroom temperature overnight and partitioned between dichloromethane andwater. The combined organic extracts were washed with brine, dried, andevaporated. The residue was purified by flash column chromatography onsilica gel, eluting with EtOAc/n-Hexane (30/70) to afford the titleproduct.

LC/MS (m/z) [M]⁺ 394.2 (calculated for C₁₉H₂₇N₃O₆, 393.19).

B. 2-Methoxycarbamoyl-piperazine-1-carboxylic acid tert-butyl ester Amixture of 2-Methoxycarbamoyl-piperazine-1,4-dicarboxylic acid 4-benzylester 1-tert-butyl ester (0.23 g, 0.58 mmol) and activated 10 wt. %palladium on carbon (0.048 g) in methanol (8 mL) was stirred vigorouslyunder 40 psi hydrogen atmosphere for 2 hours. The reaction mixture wasthen filtered through a microglass filter paper and the solid washedabundantly with methanol. The solvent was evaporated in vacuo to yieldthe title compound.

LC/MS (m/z) [M]⁺ 260.3 (calculated for C₁₁H₂₁N₃O₄, 259.15).

C.4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-methoxycarbamoyl-piperazine-1-carboxylicacid tert-butyl ester was prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 2-Methoxycarbamoyl-piperazine-1-carboxylic acid tert-butyl esterfollowing General Procedure C.

LC/MS (m/z) [M]⁺ 679.3 (calculated for C₃₀H₃₀ClF₃N₆O₆S, 678.16).

D.4-[5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-N-methoxypiperazine-2-carboxamidewas prepared from4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-methoxycarbamoyl-piperazine-1-carboxylicacid tert-butyl ester following General Procedure H.

¹H NMR (400 MHz, DMSO-d₆) δ 11.50-11.30 (br s, 1H), 8.33, 8.30 (s, 1H),8.11 (s, 1H), 7.86 (d, 1H), 7.77-7.73 (m, 2H), 7.69-7.62 (m, 2H), 6.73(d, 1H), 5.84 (s, 2H), 4.45-3.42 (m, 7H), 3.10-2.67 (m, 3H).

LC/MS (m/z) [M]⁺ 579.2 (calculated for C₂₆H₂₂ClF₃N₆O₃S, 578.1).

Example 2724-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-N-methoxypiperazine-2-carboxamide

A.4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-methoxycarbamoyl-piperazine-1-carboxylicacid tert-butyl ester was prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 2-Methoxycarbamoyl-piperazine-1-carboxylic acid tert-butyl esterfollowing General Procedure C.

LC/MS (m/z) [M]⁺ 713.4 (calculated for C₃₁H₃₀F₆N₆O₅S, 712.19).

B.4-[5-{1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-N-methoxypiperazine-2-carboxamidewas prepared from4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-methoxycarbamoyl-piperazine-1-carboxylicacid tert-butyl ester following General Procedure H.

¹H NMR (400 MHz, DMSO-d₆) δ 11.52-11.35 (br s, 1H), 8.40, 8.37 (s, 1H),8.19 (s, 1H), 8.11 (s, 1H), 7.97 (d, 2H), 7.84-7.81 (m, 2H), 7.72 (dd,1H), 6.90 (d, 1H), 5.96 (s, 2H), 4.48-3.46 (m, 7H), 3.10-2.67 (m, 3H).

LC/MS (m/z) [M]⁺ 613.2 (calculated for C₂₆H₂₂ClF₃N₆O₃S, 612.1).

Example 2734-[5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]piperazine-2-carboxamide

4-[5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]piperazine-2-carboxamidewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand piperazine-2-carboxylic acid amide following General Procedure C.

¹H NMR (400 MHz, CDCl₃) δ 8.22, 8.18 (s, 1H), 7.99-7.92 (m, 2H), 7.71(d, 1H), 7.54 (dd, 2H), 7.35-7.29 (m, 2H), 6.99-6.61 (m, 2H), 5.79 (s,2H), 5.55 (br s, 1H), 4.71-4.23 (m, 1H), 3.93-2.98 (m, 6H).

LC/MS (m/z) [M]⁺ 549.1 (calculated for C₂₄H₂₀ClF₃N₆O₂S, 548.1).

Example 2744-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]piperazine-2-carboxamide

4-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]piperazine-2-carboxamidewas prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand piperazine-2-carboxylic acid amide following General Procedure C.

¹H NMR (400 MHz, CDCl₃) δ 8.25, 8.21 (s, 1H), 8.01-7.93 (m, 3H), 7.63(d, 1H), 7.31 (d, 1H), 6.99-6.58 (m, 2H), 5.88 (s, 2H), 5.54 (br s1H),4.70-4.22 (m, 1H), 3.93-2.98 (m, 6H).

LC/MS (m/z) [M]⁺ 583.1 (calculated for C₂₅H₂₀F₆N₆O₂S, 582.1).

Example 2752-[(2R)-2-(Hydroxymethyl)morpholin-4-yl]-5-({1-[4-(1-methylethenyl)-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazol-4(5H)-one

A solution of5-{1-[4-(1-Hydroxy-1-methyl-ethyl)-2-trifluoromethyl-benzyl]-1H-indazol-5-ylmethylene}-2-(2-hydroxymethyl-morpholin-4-yl)-thiazol-4-one(400 mg, 0.71 mmol) in dichloromethane (2 mL) was treated with TFA (2mL). The reaction mixture was stirred at room temperature for 1.5 hourand partitioned between water and dichloromethane. The dichloromethanelayer was washed with aqueous saturated sodium carbonate, brine, driedover Na₂SO₄, filtered, and the solvent evaporated in vacuo to yield acrude solid. The crude solid was purified via flash chromatography (90%ethyl acetate in Heptane) to yield the title compound as a solid (94 mg,24% yield).

¹H NMR (400 MHz, CDCl₃) δ 8.19 (d, 1H), 7.97 (s, 1H), 7.96 (s, 1H), 7.79(d, 1H), 7.52 (d, 1H), 7.42 (dd, 1H), 7.33 (d, 1H), 6.66 (d, 1H), 5.83(s, 2H), 5.38 (s, 1H), 5.15 (t, 1H), 4.81 (t, 1H), 4.11 (ddd, 1H),3.84-3.25 (m, 7H), 2.11 (d, 3H).

LC/MS (m/z) [M]⁺ 543.3 (calculated for C₂₇H₂₅F₃N₄O₃S, 542.16).

Example 2761-[5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-3-methyl-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]piperidine-4-carboxylicacid

1-[5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-3-methyl-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]piperidine-4-carboxylicacid was prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-3-methyl-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand Piperidine-4-carboxylic acid following General Procedure C. Thecompound was then prepared as an ethanolamine salt.

¹H NMR (400 MHz, CD₃OD): δ 8.02 (s, 1H), 7.86 (s, 1H), 7.79 (d, 1H),7.67 (dd, 1H), 7.50 (d, 1H), 7.48 (d, 1H), 6.65 (d, 1H), 5.78 (s, 2H),4.65 and 3.96 (d, 1H, rotamer), 3.71 (t, 2H, ethanolamine salt), 3.53(t, 1H), 3.43 (t, 1H), 2.98 (m, 2H, ethanolamine salt), 2.63 (s, 3H),2.51 (br, 1H), 2.00-2.13 (3H), 1.81 (m, 2H).

LC/MS (m/z) [M]⁺ 563.25 (calculated for C₂₆H₂₂ClF₃N₄O₃S, 562.11).

Example 2775-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-3-methyl-1H-indazol-5-yl}methylidene)-2-[(3S)-3-(hydroxymethyl)piperazin-1-yl]-1,3-thiazol-4(5H)-one

A.4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-3-methyl-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester was prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-3-methyl-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 2-Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl esterfollowing General Procedure C.

LC/MS (m/z) [M]⁺ 650.3 (calculated for C₃₀H₃₁ClF₃N₅O₄S, 649.17).

B.5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-3-methyl-1H-indazol-5-yl}methylidene)-2-[(3S)-3-(hydroxymethyl)piperazin-1-yl]-1,3-thiazol-4(5H)-onewas prepared from4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-3-methyl-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester following General Procedure H.

¹H NMR (400 MHz, CD₃OD): δ 8.06 (s, 1H), 7.97 (s, 1H), 7.80 (s, 1H),7.68 (d, 1H), 7.51 (d, 1H), 7.48 (d, 1H), 6.69 (d, 1H), 5.78 (s, 2H),4.16 (m, 1H), 3.87 (m, 1H), 3.76 (m, 2H), 3.65-3.12 (5H), 2.62 (s, 3H).

LC/MS (m/z) [M]⁺ 550.8 (calculated for C₂₅H₂₃ClF₃N₅O₂S, 549.12).

Example 2785-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-3-methyl-1H-indazol-5-yl}methylidene)-2-(3,3,4-trimethylpiperazin-1-yl)-1,3-thiazol-4(5H)-one

5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-3-methyl-1H-indazol-5-yl}methylidene)-2-(3,3,4-trimethylpiperazin-1-yl)-1,3-thiazol-4(5H)-onewas prepared from5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-3-methyl-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand 1,2,2-Trimethyl-piperazine following General Procedure C.

¹H NMR (400 MHz, CD₃OD): δ 7.98 (s, 1H), 7.95 (d, 1H), 7.78 (d, 1H),7.62 (d, 1H), 7.48 (d, 1H), 7.46 (d, 1H), 6.68 (t, 1H), 5.73 (d, 2H,rotamers), 4.82 and 4.70 (d, 1H, rotamers), 4.23 and 3.73 (d, 1H,rotamers), 4.13 (m, 1H), 3.93 (m, 1H), 3.61 (m, 2H), 2.91 (s, 3H), 2.60(d, 3H, rotamers), 1.62 (d, 3H, rotamers), 1.46 (d, 3H, rotamers).

LC/MS (m/z) [M]⁺ 562.20 (calculated for C₂₇H₂₇ClF₃N₅OS, 561.16).

Example 279 tert-Butyl(2R)-4-[5-({1-[2,4-bis(trifluoromethyl)benzyl]-3-iodo-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-2-(hydroxymethyl)piperazine-1-carboxylate

4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-iodo-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester was prepared from1-(2,4-Bis-trifluoromethyl-benzyl)-3-iodo-1H-indazole-5-carbaldehyde and2-Hydroxymethyl-4-(4-oxo-4,5-dihydro-thiazol-2-yl)-piperazine-1-carboxylicacid tert-butyl ester following General Procedure D.

¹H NMR (400 MHz, CD₃OD): δ 8.00 (s, 1H), 7.75 (br, 1H), 7.61 (d, 1H),7.54 (d, 1H), 7.45 (m, 1H), 7.40 (m, 1H), 6.88 (t, 1H), 5.83 (s, 2H),4.70 and 4.54 (d, 1H, rotamers), 4.31 (br, 1H), 4.11 and 3.82 (d, 1H,rotamers), 4.04 (d, 1H), 3.54-3.74 (3H), 3.42 (m, 1H), 3.25 (br, 1H),1.50 (s, 9H).

LC/MS (m/z) [M]⁺ 796.05 (calculated for C₃₀H₂₈F₆₁N₅O₄S, 795.08).

Example 280{(2S)-4-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]morpholin-2-yl}methylacetate

{(2S)-4-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]morpholin-2-yl}methylacetate was prepared from1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde andMorpholin-2-yl-methanol following General Procedure E.

¹H NMR (400 MHz, CDCl₃) δ 8.22 (d, 1H), 7.99 (br s, 2H), 7.97 (s, 1H),7.63 (d, 1H), 7.56 (d, 1H), 7.33-7.31 (m, 1H), 6.83 (d, 1H), 5.89 (s,2H), 4.89 (d, 0.5H), 4.79 (d, 0.5H), 4.25-4.08 (m, 3H), 3.84-3.81 (m,1H), 3.76-3.67 (m, 2H), 3.64-3.57 (m, 0.5H), 3.43-3.37 (m. 0.5H),3.22-3.17 (m, 0.5H), 2.15 and 2.12 (2s, 3H).

LC/MS (m/z) [M+1]⁺ 613.2 (calculated for C₂₇H₂₂F₆N₄O₄S, 612.13).

Example 2812-[(2S)-2-(Hydroxymethyl)morpholin-4-yl]-5-[(1-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-1H-indazol-5-yl)methylidene]-1,3-thiazol-4(5H)-one

A. 1-(3-Trifluoromethyl-pyridin-2-ylmethyl)-1H-indazole-5-carbaldehydewas prepared from 1H-Indazole-5-carbaldehyde and2-Chloromethyl-3-trifluoromethyl-pyridine following General Procedure A.

¹H NMR (400 MHz, CDCl₃) δ 10.06 (s, 1H), 8.59 (d, 1H), 8.29 (s, 1H),8.25 (s, 1H), 8.03 (d, 1H), 7.94 (d, 1H), 7.48 (d, 1H), 7.37-7.33 (m,1H), 5.94 (s, 2H).

LC/MS (m/z) [M+1]⁺ 306.1 (calculated for C₁₅H₁₀F₃N₃O, 305.08).

B.2-[(2S)-2-(Hydroxymethyl)morpholin-4-yl]-5-[(1-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-1H-indazol-5-yl)methylidene]-1,3-thiazol-4(5H)-onewas prepared from1-(3-Trifluoromethyl-pyridin-2-ylmethyl)-1H-indazole-5-carbaldehyde and2(S)-(2-Hydroxymethyl-morpholin-4-yl)-thiazol-4-one following GeneralProcedure D.

¹H NMR (400 MHz, CDCl₃) δ 8.61 (d, 1H), 8.16 (d, 1H), 8.02 (d, 1H), 7.96(br s, 2H), 7.53 (d, 1H), 7.44 (d, 1H), 7.36-7.33 (m, 1H), 5.91 (s, 2H),4.84-4.78 (m, 1H), 4.15-4.06 (ddd, 1H), 3.85-3.56 (m, 5.5H), 3.52-3.46(m, 0.5H), 3.41-3.33 (m, 0.5H), 3.30-3.24 (m, 0.5H), 1.94-1.88 (m, 1H).

LC/MS (m/z) [M+1]⁺ 504.1 (calculated for C₂₃H₂₀F₃N₅O₃S, 503.12).

Example 282 MethylN—({(2S)-4-[5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]morpholin-2-yl}carbonyl)glycinate

A. 2-(Methoxycarbonylmethyl-carbamoyl)-morpholine-4-carboxylic acidtert-butyl ester.

To a solution of Morpholine-2,4-dicarboxylic acid 4-tert-butyl ester(0.3 g, 1.29 mmol), glycine methyl ester hydrochloride (0.162 g, 1.29mmol) and diisopropylethylamine (0.167 g, 1.29 mmol) in dichloromethane(8 mL) and THF (4 mL) was added EDCI (0.274 g, 1.43 mmol) followed byDMAP (0.048 g, 0.39 mmol).

The reaction mixture was stirred at room temperature for 48 hours andthe solvent evaporated in vacuo to give a solid. The solid waspartitioned between dichloromethane and an aqueous 5% citric acidsolution. The dichloromethane layer was washed with aqueous saturatedsodium carbonate, brine, dried over Na₂SO₄, filtered, and the solventevaporated in vacuo to yield the title compound as a colorless gum (0.25g, 64% yield).

¹H NMR (400 MHz, CDCl₃) δ 7.06 (br s, 1H), 4.33 (br s, 1H), 4.07 (d,2H), 3.99-3.93 (m, 3H), 3.77 (s, 3H), 2.93-2.91 (m, 1H), 2.81-2.75 (m,1H), 1.47 (s, 9H).

LC/MS (m/z) [MNa]⁺ 325.2 (calculated for C₁₃H₂₂N₂O₆, 302.15).

B. [(Morpholine-2-carbonyl)-amino]-acetic acid methyl ester was preparedfollowing General Procedure I.

¹H NMR (400 MHz, D₂O) δ 4.37 (dd, 1H), 4.13-4.09 (m, 1H), 3.95 (s, 2H),3.87-3.79 (m, 1H), 3.62 (s, 3H), 3.52-3.49 (m, 1H), 3.27-3.24 (m, 1H),3.15-3.06 (m, 2H).

LC/MS (m/z) [M]⁺ 203.1 (calculated for C₈H₁₄N₂O₄, 202.1).

C. MethylN—({(2S)-4-[5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]morpholin-2-yl}carbonyl)glycinatewas prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-oneand [(Morpholine-2-carbonyl)-amino]-acetic acid methyl ester followingGeneral Procedure B.

¹H NMR (400 MHz, CDCl₃) δ 8.26 (d, 1H), 8.01-7.95 (m, 3H), 7.63 (d, 1H),7.55 (d, 1H), 7.33 (d, 1H), 7.12-7.10 (m, 1H), 6.82 (d, 1H), 5.89 (s,2H), 4.79-4.75 (m, 1H), 4.19-4.11 (m, 5H), 3.81-3.76 (m, 4H), 3.50-3.40(m, 2H).

LC/MS (m/z) [M+1]⁺ 656.2 (calculated for C₂₈H₂₃F₆N₅O₅S, 655.13).

Example 2835-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-(S)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one

A.4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(S)-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester was prepared from5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-oneand (2S)—Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl esterfollowing General Procedure C.

LC/MS (m/z) [M+1]⁺ 670.3 (calculated for C₃₀H₂₉F₆N₅O₄S, 669.18).

B.5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-(S)-hydroxymethyl-piperazin-1-yl)thiazol-4-onewas prepared from4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(S)-hydroxymethyl-piperazine-1-carboxylicacid tert-butyl ester following General Procedure H.

¹H NMR (400 MHz, CDCl₃): δ 8.22 (dd, 1H), 7.99 (br, 2H), 7.94 (s, 1H),7.63 (d, 1H), 7.56 (m, 1H), 7.32 (d, 1H), 6.82 (d, 1H), 5.88 (s, 2H),4.77 (m, 1H), 3.78-3.72 (2H), 3.70-3.55 (1H), 3.53-3.15 (3H), 3.05-2.92(2H), 2.01 (br s, 1H).

LC/MS (m/z) [M+1]⁺ 570.5 (calculated for C₂₅H₂₁F₆N₅O₂S, 569.13).

D) General Administration, Formulation, and Dosages

The present compounds are ERR-α modulators and are therefore useful intreating, preventing, or inhibiting the progression of ERR-α mediatedconditions including but not limited to ankylosing spondylitis,artherosclerosis, arthritis (such as rheumatoid arthritis, infectiousarthritis, childhood arthritis, psoriatic arthritis, reactivearthritis), bone-related diseases (including those related to boneformation), breast cancer (including those unresponsive to anti-estrogentherapy), cardiovascular disorders, cartilage-related disease (such ascartilage injury/loss, cartilage degeneration, and those related tocartilage formation), chondrodysplasia, chondrosarcoma, chronic backinjury, chronic bronchitis, chronic inflammatory airway disease, chronicobstructive pulmonary disease, diabetes, disorders of energyhomeostasis, gout, pseudogout, lipid disorders, metabolic syndrome,multiple myeloma, obesity, osteoarthritis, osteogenesis imperfecta,osteolytic bone metastasis, osteomalacia, osteoporosis, Paget's disease,periodontal disease, polymyalgia rheumatica, Reiter's syndrome,repetitive stress injury, hyperglycemia, elevated blood glucose level,and insulin resistance and other disorders, diseases, or conditionsrelated thereto.

The invention features a method for treating a subject with an ERR-αmediated disease, said method comprising administering to the subject atherapeutically effective amount of a pharmaceutical compositioncomprising a compound of the invention. In particular, the inventionalso provides a method for treating or inhibiting the progression ofbreast cancer, arthritis, inflammatory airway disease, or metabolicdisorders, and associated symptoms or complications thereof in asubject, wherein the method comprises administering to the subject atherapeutically effective amount of a pharmaceutical compositioncomprising a compound of the invention.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds which are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the subject. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

Some of the crystalline forms for the compounds may exist as polymorphsand as such are intended to be included in the present invention. Inaddition, some of the compounds may form solvates with water (i.e.,hydrates) or common organic solvents, and such solvates are intended tobe encompassed within the scope of this invention.

Where the processes for the preparation of the compounds according tothe invention give rise to mixtures of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form or asindividual enantiomers or diasteromers by either stereospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers or diastereomers by standardtechniques, such as the formation of stereoisomeric pairs by saltformation with an optically active base, followed by fractionalcrystallization and regeneration of the free acid. The compounds mayalso be resolved by formation of stereoisomeric esters or amides,followed by chromatographic separation and removal of the chiralauxiliary. Alternatively, the compounds may be resolved using a chiralHPLC column. It is to be understood that all stereoisomers, racemicmixtures, diastereomers, cis-trans isomers, and enantiomers thereof areencompassed within the scope of the present invention.

E) Use

1. Dosages

Those of skill in the treatment of disorders, diseases, or conditionsmediated by ERR-α can determine the effective daily amount from the testresults presented hereinafter and other information. The exact dosageand frequency of administration depends on the particular compound ofinvention used, the particular condition being treated, the severity ofthe condition being treated, the age, weight and general physicalcondition of the particular patient as well as other medication thepatient may be taking, as is well known to those skilled in the art.Furthermore, it is evident that said effective daily amount may belowered or increased depending on the response of the treated patientand/or depending on the evaluation of the physician prescribing thecompounds of the instant invention. The effective daily amount rangesmentioned herein are therefore only guidelines in practicing the presentinvention.

Preferably, the method for the treatment of the ERR-α disordersdescribed in the present invention using any of the compounds as definedherein, the dosage form will contain a pharmaceutically acceptablecarrier containing between from about 0.1 mg to about 5000 mg;particularly from about 0.5 mg to about 1000 mg; and, more particularly,from about 1 mg to about 100 mg of the compound, and may be constitutedinto any form suitable for the mode of administration selected. Thedosages, however, may be varied depending upon the requirement of thesubjects, the severity of the condition being treated and the compoundbeing employed. The use of either daily administration or post-periodicdosing may be employed.

The pharmaceutical compositions herein will contain, per unit dosageunit, e.g., tablet, capsule, powder, injection, suppository, teaspoonfuland the like, of from about 0.001 mg/kg/day to about 10 mg/kg/day(particularly from about 0.01 mg/kg/day to about 1 mg/kg/day; and, moreparticularly, from about 0.1 mg/kg/day to about 0.5 mg/kg/day) and maybe given at a dosage of from about 0.001 mg/kg/day to about 30 mg/kg/day(particularly from about 0.01 mg/kg/day to about 2 mg/kg/day, moreparticularly from about 0.1 mg/kg/day to about 1 mg/kg/day and even moreparticularly from about 0.5 mg/kg/day to about 1 mg/kg/day).

Preferably these compositions are in unit dosage forms from such astablets, pills, capsules, dry powders for reconstitution or inhalation,granules, lozenges, sterile parenteral solutions or suspensions, meteredaerosol or liquid sprays, drops, ampoules, autoinjector devices orsuppositories for administration by oral, intranasal, sublingual,intraocular, transdermal, parenteral, rectal, vaginal, dry powderinhaler or other inhalation or insufflation means. Alternatively, thecomposition may be presented in a form suitable for once-weekly oronce-monthly administration; for example, an insoluble salt of theactive compound, such as the decanoate salt, may be adapted to provide adepot preparation for intramuscular injection.

For preparing solid pharmaceutical compositions such as tablets, theprincipal active ingredient is mixed with a pharmaceutical carrier, e.g.conventional tableting ingredients such as diluents, binders, adhesives,disintegrants, lubricants, antiadherents and gildants. Suitable diluentsinclude, but are not limited to, starch (i.e. corn, wheat, or potatostarch, which may be hydrolized), lactose (granulated, spray dried oranhydrous), sucrose, sucrose-based diluents (confectioner's sugar;sucrose plus about 7 to 10 weight percent invert sugar; sucrose plusabout 3 weight percent modified dextrins; sucrose plus invert sugar,about 4 weight percent invert sugar, about 0.1 to 0.2 weight percentcornstarch and magnesium stearate), dextrose, inositol, mannitol,sorbitol, microcrystalline cellulose (i.e. AVICEL™ microcrystallinecellulose available from FMC Corp.), dicalcium phosphate, calciumsulfate dihydrate, calcium lactate trihydrate and the like. Suitablebinders and adhesives include, but are not limited to acacia gum, guargum, tragacanth gum, sucrose, gelatin, glucose, starch, and cellulosics(i.e. methylcellulose, sodium carboxymethylcellulose, ethylcellulose,hydroxypropylmethylcellulose, hydroxypropylcellulose, and the like),water soluble or dispersible binders (i.e. alginic acid and saltsthereof, magnesium aluminum silicate, hydroxyethylcellulose [i.e.TYLOSE™ available from Hoechst Celanese], polyethylene glycol,polysaccharide acids, bentonites, polyvinylpyrrolidone,polymethacrylates and pregelatinized starch) and the like. Suitabledisintegrants include, but are not limited to, starches (corn, potato,etc.), sodium starch glycolates, pregelatinized starches, clays(magnesium aluminum silicate), celluloses (such as crosslinked sodiumcarboxymethylcellulose and microcrystalline cellulose), alginates,pregelatinized starches (i.e. corn starch, etc.), gums (i.e. agar, guar,locust bean, karaya, pectin, and tragacanth gum), cross-linkedpolyvinylpyrrolidone and the like. Suitable lubricants and antiadherentsinclude, but are not limited to, stearates (magnesium, calcium andsodium), stearic acid, talc waxes, stearowet, boric acid, sodiumchloride, DL-leucine, carbowax 4000, carbowax 6000, sodium oleate,sodium benzoate, sodium acetate, sodium lauryl sulfate, magnesium laurylsulfate and the like. Suitable gildants include, but are not limited to,talc, cornstarch, silica (i.e. CAB-O-SIL™ silica available from Cabot,SYLOID™ silica available from W.R. Grace/Davison, and AEROSIL™ silicaavailable from Degussa) and the like. Sweeteners and flavorants may beadded to chewable solid dosage forms to improve the palatability of theoral dosage form. Additionally, colorants and coatings may be added orapplied to the solid dosage form for ease of identification of the drugor for aesthetic purposes. These carriers are formulated with thepharmaceutical active to provide an accurate, appropriate dose of thepharmaceutical active with a therapeutic release profile.

Generally these carriers are mixed with the pharmaceutical active toform a solid preformulation composition containing a homogeneous mixtureof the pharmaceutical active form of the present invention, or apharmaceutically acceptable salt thereof. Generally the preformulationwill be formed by one of three common methods: (a) wet granulation, (b)dry granulation and (c) dry blending. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective dosageforms such as tablets, pills and capsules. This solid preformulationcomposition is then subdivided into unit dosage forms of the typedescribed above containing from about 0.1 mg to about 500 mg of theactive ingredient of the present invention. The tablets or pillscontaining the novel compositions may also be formulated in multilayertablets or pills to provide a sustained or provide dual-releaseproducts. For example, a dual release tablet or pill can comprise aninner dosage and an outer dosage component, the latter being in the formof an envelope over the former. The two components can be separated byan enteric layer, which serves to resist disintegration in the stomachand permits the inner component to pass intact into the duodenum or tobe delayed in release. A variety of materials can be used for suchenteric layers or coatings, such materials including a number ofpolymeric materials such as shellac, cellulose acetate (i.e. celluloseacetate phthalate, cellulose acetate trimellitate), polyvinyl acetatephthalate, hydroxypropyl methylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, methacrylate and ethylacrylatecopolymers, methacrylate and methyl methacrylate copolymers and thelike. Sustained release tablets may also be made by film coating or wetgranulation using slightly soluble or insoluble substances in solution(which for a wet granulation acts as the binding agents) or low meltingsolids a molten form (which in a wet granulation may incorporate theactive ingredient). These materials include natural and syntheticpolymers waxes, hydrogenated oils, fatty acids and alcohols (i.e.beeswax, carnauba wax, cetyl alcohol, cetylstearyl alcohol, and thelike), esters of fatty acids metallic soaps, and other acceptablematerials that can be used to granulate, coat, entrap or otherwise limitthe solubility of an active ingredient to achieve a prolonged orsustained release product.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude, but are not limited to aqueous solutions, suitably flavoredsyrups, aqueous or oil suspensions, and flavored emulsions with edibleoils such as cottonseed oil, sesame oil, coconut oil or peanut oil, aswell as elixirs and similar pharmaceutical vehicles. Suitable suspendingagents for aqueous suspensions, include synthetic and natural gums suchas, acacia, agar, alginate (i.e. propylene alginate, sodium alginate andthe like), guar, karaya, locust bean, pectin, tragacanth, and xanthangum, cellulosics such as sodium carboxymethylcellulose, methylcellulose,hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropyl celluloseand hydroxypropyl methylcellulose, and combinations thereof, syntheticpolymers such as polyvinyl pyrrolidone, carbomer (i.e.carboxypolymethylene), and polyethylene glycol; clays such as bentonite,hectorite, attapulgite or sepiolite; and other pharmaceuticallyacceptable suspending agents such as lecithin, gelatin or the like.Suitable surfactants include but are not limited to sodium docusate,sodium lauryl sulfate, polysorbate, octoxynol-9, nonoxynol-10,polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80,polyoxamer 188, polyoxamer 235 and combinations thereof. Suitabledeflocculating or dispersing agent include pharmaceutical gradelecithins. Suitable flocculating agent include but are not limited tosimple neutral electrolytes (i.e. sodium chloride, potassium, chloride,and the like), highly charged insoluble polymers and polyelectrolytespecies, water soluble divalent or trivalent ions (i.e. calcium salts,alums or sulfates, citrates and phosphates (which can be used jointly informulations as pH buffers and flocculating agents). Suitablepreservatives include but are not limited to parabens (i.e. methyl,ethyl, n-propyl and n-butyl), sorbic acid, thimerosal, quaternaryammonium salts, benzyl alcohol, benzoic acid, chlorhexidine gluconate,phenylethanol and the like. There are many liquid vehicles that may beused in liquid pharmaceutical dosage forms, however, the liquid vehiclethat is used in a particular dosage form must be compatible with thesuspending agent(s). For example, nonpolar liquid vehicles such as fattyesters and oils liquid vehicles are best used with suspending agentssuch as low HLB (Hydrophile-Lipophile Balance) surfactants,stearalkonium hectorite, water insoluble resins, water insoluble filmforming polymers and the like. Conversely, polar liquids such as water,alcohols, polyols and glycols are best used with suspending agents suchas higher HLB surfactants, clays silicates, gums, water solublecellulosics, water soluble polymers and the like. For parenteraladministration, sterile suspensions and solutions are desired. Liquidforms useful for parenteral administration include sterile solutions,emulsions and suspensions. Isotonic preparations which generally containsuitable preservatives are employed when intravenous administration isdesired.

Furthermore, compounds of the present invention can be administered inan intranasal dosage form via topical use of suitable intranasalvehicles or via transdermal skin patches, the composition of which arewell known to those of ordinary skill in that art. To be administered inthe form of a transdermal delivery system, the administration of atherapeutic dose will, of course, be continuous rather than intermittentthroughout the dosage regimen.

Compounds of the present invention can also be administered in the formof liposome delivery systems, such as small unilamellar vesicles, largeunilamellar vesicles, multilamellar vesicles and the like. Liposomes canbe formed from a variety of phospholipids, such as cholesterol,stearylamine, phosphatidylcholines and the like.

The daily dose of a pharmaceutical composition of the present inventionmay be varied over a wide range from about 0.1 mg to about 5000 mg;preferably, the dose will be in the range of from about 1 mg to about100 mg per day for an average human. For oral administration, thecompositions are preferably provided in the form of tablets containing,0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150,200, 250 or 500 milligrams of the active ingredient for the symptomaticadjustment of the dosage to the subject to be treated. Advantageously, acompound of the present invention may be administered in a single dailydose or the total daily dosage may be administered in divided doses oftwo, three or four times daily.

It is also apparent to one skilled in the art that the therapeuticallyeffective dose for active compounds of the invention or a pharmaceuticalcomposition thereof will vary according to the desired effect.Therefore, optimal dosages to be administered may be readily determinedby those skilled in the art, and will vary with the particular compoundused, the mode of administration, the strength of the preparation, andthe advancement of the disease condition. In addition, factorsassociated with the particular subject being treated, including subjectage, weight, diet and time of administration, will result in the need toadjust the dose to an appropriate therapeutic level. The above dosagesare thus exemplary of the average case. There can, of course, beindividual instances where higher or lower dosage ranges are merited,and such are within the scope of this invention.

Compounds of this invention may be administered in any of the foregoingcompositions and dosage regimens or by means of those compositions anddosage regimens established in the art whenever use of the compounds ofthe invention as ERR-α modulators is required for a subject in needthereof.

2. Formulations

To prepare the pharmaceutical compositions of this invention, one ormore compounds of Formula (I) or salt thereof as the active ingredient,is intimately admixed with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques, which carrier maytake a wide variety of forms depending of the form of preparationdesired for administration (e.g. oral or parenteral). Suitablepharmaceutically acceptable carriers are well known in the art.Descriptions of some of these pharmaceutically acceptable carriers maybe found in The Handbook of Pharmaceutical Excipients, published by theAmerican Pharmaceutical Association and the Pharmaceutical Society ofGreat Britain.

The compounds of the present invention may be formulated into variouspharmaceutical forms for administration purposes. Methods of formulatingpharmaceutical compositions have been described in numerous publicationssuch as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revisedand Expanded, Volumes 1-3, edited by Lieberman et al; PharmaceuticalDosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al;and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, editedby Lieberman et al; published by Marcel Dekker, Inc.

3. Combination Therapy

The compounds of the present invention may be used in combination withone or more pharmaceutically active agents. These include anti-diabeticagents, anti-obesity agents, other lipid lowering agents, directthrombin inhibitor (DTI), as well as lipid lowering agents such asstatin drugs and the fibrates.

Other agents useful for the combination therapy of the present inventioninclude glucokinase modulators such as:

Anti-diabetic agents include RXR modulators such as:

-   -   (1) bexarotene        (4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)ethenyl)benzoic        acid, known as TARGRETIN, TARGRETYN, TARGREXIN; also known as        LGD 1069, LG 100069, LG 1069, LDG 1069, LG 69, RO 264455);    -   (2) 9-cis-retinoic acid;    -   (3) AGN-4326 (also known as ALRT-4204, AGN-4204, ALRT-326,        ALRT-324, or LGD 1324);    -   (4) LGD 1324 (ALRT 324);    -   (5) LG 100754;    -   (6) LY-510929;    -   (7) LGD 1268        (6-(1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydro-naphth-7-ylcycloprop-1-yl)nicotinic        acid, known as ALRT 268 or LG 100268); and    -   (8) LG 100264.

Anti-diabetic agents also include thiazolidinedione andnon-thiazolidinedione insulin sensitizers, which decrease peripheralinsulin resistance by enhancing the effects of insulin at target organsand tissues.

The following agents are known to bind and activate the nuclear receptorperoxisome proliferator-activated receptor-gamma (PPARγ) which increasestranscription of specific insulin-responsive genes. Examples ofPPAR-gamma agonists are thiazolidinediones such as:

-   -   (1) rosiglitazone        (2,4-thiazolidinedione,5-((4-(2-(methyl-2-pyridinylamino)        ethoxy)phenyl)methyl)-, (Z)-2-butenedioate (1:1) or        5-((4-(2-(methyl-2-pyridinylamino)        ethoxy)phenyl)methyl)-2,4-thiazolidinedione, known as AVANDIA;        also known as BRL 49653, BRL 49653C, BRL 49653c, SB 210232, or        rosiglitazone maleate);    -   (2) pioglitazone (2,4-thiazolidinedione,        5-((4-(2-(5-ethyl-2-pyridinyl)ethoxy)phenyl)methyl)-,        monohydrochloride, (+−) or        5-((4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl)methy)-2,4-thiazolidinedione,        known as ACTOS, ZACTOS, or GLUSTIN; also known as AD 4833, U        72107, U 72107A, U 72107E, pioglitazone hydrochloride (USAN));    -   (3) troglitazone        (5-((4-((3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy)phenyl)methyl)-2,4-thiazolidinedione,        known as NOSCAL, REZULIN, ROMOZIN, or PRELAY; also known as        CI-991, CS 045, GR 92132, GR 92132X);    -   (4) isaglitazone        ((+)-5-[[6-[(2-fluorophenyl)methoxy]-2-naphthalenyl]methyl]-2,4-thiazolidinedione        or        5-((6-((2-fluorophenyl)methoxy)-2-naphthalenyl)methyl-2,4-thiazolidinedione        or 5-(6-(2-fluorobenzyloxy) naphthalen-2-ylmethyl)        thiazolidine-2,4-dione, also known as MCC-555 or neoglitazone);        and    -   (5) 5-BTZD.

Additionally, the non-thiazolidinediones that act as insulin sensitizingagents include, but are not limited to:

-   -   (1) JT-501 (JTT 501, PNU-1827, PNU-7,6-MET-0096, or PNU 182716:        isoxazolidine-3,5-dione,        4-((4-(2-phenyl-5-methyl)-1,3-oxazolyl)ethylphenyl-4) methyl-);    -   (2) KRP-297        (5-(2,4-dioxothiazolidin-5-ylmethyl)-2-methoxy-N-(4-(trifluoromethyl)benzyl)benzamide        or        5-((2,4-dioxo-5-thiazolidinyl)methyl)-2-methoxy-N-((4-(trifluoromethyl)phenyl)methyl)benzamide);        and    -   (3) Farglitazar (L-tyrosine,        N-(2-benzoylphenyl)-o-(2-(5-methyl-2-phenyl-4-oxazolyl)ethyl)-        or        N-(2-benzoylphenyl)-O-(2-(5-methyl-2-phenyl-4-oxazolyl)ethyl)-L-tyrosine,        or GW2570 or GI-262570).

Other anti-diabetic agents have also been shown to have PPAR modulatoractivity such as PPAR gamma, SPPAR gamma, and/or PPAR delta/gammaagonist activity. Examples are listed below:

-   -   (1) AD 5075;    -   (2) R 119702        ((+−)-5-(4-(5-Methoxy-1H-benzimidazol-2-ylmethoxy)benzyl)        thiazolin-2,4-dione hydrochloride, or CI 1037 or CS 011);    -   (3) CLX-0940 (peroxisome proliferator-activated receptor alpha        agonist/peroxisome proliferator-activated receptor gamma        agonist);    -   (4) LR-90 (2,5,5-tris (4-chlorophenyl)-1,3-dioxane-2-carboxylic        acid, PPARdelta/γ agonist);    -   (5) Tularik (PPARγ agonist);    -   (6) CLX-0921 (PPARγ agonist);    -   (7) CGP-52608 (PPAR agonist);    -   (8) GW-409890 (PPAR agonist);    -   (9) GW-7845 (PPAR agonist);    -   (10) L-764406 (PPAR agonist);    -   (11) LG-101280 (PPAR agonist);    -   (12) LM-4156 (PPAR agonist);    -   (13) Risarestat (CT-112);    -   (14) YM 440 (PPAR agonist);    -   (15) AR-H049020 (PPAR agonist);    -   (16) GW 0072        (4-(4-((2S,5S)-5-(2-(bis(phenylmethyl)amino)-2-oxoethyl)-2-heptyl-4-oxo-3-thiazolidinyl)        butyl)benzoic acid);    -   (17) GW 409544 (GW-544 or GW-409544);    -   (18) NN 2344 (DRF 2593);    -   (19) NN 622 (DRF 2725);    -   (20) AR-H039242 (AZ-242);    -   (21) GW 9820 (fibrate);    -   (22) GW 1929 (N-(2-benzoylphenyl)-O-(2-(methyl-2-pyridinylamino)        ethyl)-L-tyrosine, known as GW 2331, PPAR alpha/γ agonist);    -   (23) SB 219994        ((S)-4-(2-(2-benzoxazolylmethylamino)ethoxy)-alpha-(2,2,2-trifluoroethoxy)benzenepropanoic        acid or 3-(4-1-(2-(N-(2-benzoxazolyl)-N-methylamino)        ethoxy)phenyl)-2 (S)-(2,2,2-trifluoroethoxy) propionic acid or        benzenepropanoic acid, 4-(2-(2-benzoxazolylmethylamino)        ethoxy)-alpha-(2,2,2-trifluoroethoxy)-, (alphaS)-, PPARalpha/γ        agonist);    -   (24) L-796449 (PPAR alpha/γ agonist);    -   (25) Fenofibrate (Propanoic acid,        2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-, 1-methylethyl ester,        known as TRICOR, LIPCOR, LIPANTIL, LIPIDIL MICRO PPAR alpha        agonist);    -   (26) GW-9578 (PPAR alpha agonist);    -   (27) GW-2433 (PPAR alpha/γ agonist);    -   (28) GW-0207 (PPARγ agonist);    -   (29) LG-100641 (PPARγ agonist);    -   (30) LY-300512 (PPARγ agonist);    -   (31) NID525-209 (NID-525);    -   (32) VDO-52 (VDO-52);    -   (33) LG 100754 (peroxisome proliferator-activated receptor        agonist);    -   (34) LY-510929 (peroxisome proliferator-activated receptor        agonist);    -   (35) bexarotene        (4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)ethenyl)benzoic        acid, known as TARGRETIN, TARGRETYN, TARGREXIN; also known as        LGD 1069, LG 100069, LG 1069, LDG 1069, LG 69, RO 264455); and    -   (36) GW-1536 (PPAR alpha/γ agonist).

Other insulin sensitizing agents include, but are not limited to:

-   -   (1) INS-1 (D-chiro inositol or        D-1,2,3,4,5,6-hexahydroxycyclohexane);    -   (2) protein tyrosine phosphatase 1 B (PTP-1 B) inhibitors;    -   (3) glycogen synthase kinase-3 (GSK3) inhibitors;    -   (4) beta 3 adrenoceptor agonists such as ZD 2079        ((R)—N-(2-(4-(carboxymethyl)phenoxy)ethyl)-N-(2-hydroxy-2-phenethyl)        ammonium chloride, also known as ICI D 2079) or AZ 40140;    -   (5) glycogen phosphorylase inhibitors;    -   (6) fructose-1,6-bisphosphatase inhibitors;    -   (7) chromic picolinate, vanadyl sulfate (vanadium oxysulfate);    -   (8) KP 102 (organo-vanadium compound);    -   (9) chromic polynicotinate;    -   (10) potassium channel agonist NN 414;    -   (11) YM 268 (5, 5′-methylene-bis(1,4-phenylene)bismethylenebis        (thiazolidine-2,4-dione);    -   (12) TS 971;    -   (13) T 174        ((+−)-5-(2,4-dioxothiazolidin-5-ylmethyl)-2-(2-naphthylmethyl)benzoxazole);    -   (14) SDZ PGU 693 ((+)-trans-2        (S—((4-chlorophenoxy)methyl)-7alpha-(3,4-dichlorophenyl)tetrahydropyrrolo        (2,1-b) oxazol-5(6H)-one);    -   (15) S15261 ((−)-4-(2-((9H-fluoren-9-ylacetyl)amino)        ethyl)benzoic acid        2-((2-methoxy-2-(3-(trifluoromethyl)phenyl)ethyl)amino) ethyl        ester);    -   (16) AZM 134 (Alizyme);    -   (17) ARIAD;    -   (18) R 102380;    -   (19) PNU 140975 (1-(hydrazinoiminomethyl) hydrazino) acetic        acid;    -   (20) PNU 106817 (2-(hydrazinoiminomethyl) hydrazino) acetic        acid;    -   (21) NC 2100        (5-((7-(phenylmethoxy)-3-quinolinyl)methyl)-2,4-thiazolidinedione;    -   (22) MXC 3255;    -   (23) MBX 102;    -   (24) ALT 4037;    -   (25) AM 454;    -   (26) JTP 20993        (2-(4-(2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy)benzyl)-malonic        acid dimethyl diester);    -   (27) Dexlipotam (5(R)-(1,2-dithiolan-3-yl) pentanoic acid, also        known as (R)-alpha lipoic acid or (R)-thioctic acid);    -   (28) BM 170744 (2,2-Dichloro-12-(p-chlorophenyl) dodecanoic        acid);    -   (29) BM 152054 (5-(4-(2-(5-methyl-2-(2-thienyl)        oxazol-4-yl)ethoxy)benzothien-7-ylmethyl)        thiazolidine-2,4-dione);    -   (30) BM 131258        (5-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)benzothien-7-ylmethyl)thiazolidine-2,4-dione);    -   (31) CRE 16336 (EML 16336);    -   (32) HQL 975        (3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)phenyl)-2(S)-(propylamino)        propionic acid);    -   (33) DRF 2189 (5-((4-(2-(1-Indolyl)ethoxy)phenyl)methyl)        thiazolidine-2,4-dione);    -   (34) DRF 554158;    -   (35) DRF-NPCC;    -   (36) CLX 0100, CLX 0101, CLX 0900, or CLX 0901;    -   (37) IkappaB Kinase (IKK B) Inhibitors;    -   (38) mitogen-activated protein kinase (MAPK) inhibitors p38 MAPK        Stimulators;    -   (39) phosphatidyl-inositide triphosphate;    -   (40) insulin recycling receptor inhibitors;    -   (41) glucose transporter 4 modulators;    -   (42) TNF-α antagonists;    -   (43) plasma cell differentiation antigen-1 (PC-1) Antagonists;    -   (44) adipocyte lipid-binding protein (ALBP/aP2) inhibitors;    -   (45) phosphoglycans;    -   (46) Galparan;    -   (47) Receptron;    -   (48) islet cell maturation factor;    -   (49) insulin potentiating factor (IPF or insulin potentiating        factor-1);    -   (50) somatomedin C coupled with binding protein (also known as        IGF-BP3, IGF-BP3, SomatoKine);    -   (51) Diab II (known as V-411) or Glucanin, produced by Biotech        Holdings Ltd. or Volque Pharmaceutical;    -   (52) glucose-6 phosphatase inhibitors;    -   (53) fatty acid glucose transport protein;    -   (54) glucocorticoid receptor antagonists; and    -   (55) glutamine:fructose-6-phosphate amidotransferase (GFAT)        modulators.

Anti-diabetic agents can further include biguanides, which decreasesliver glucose production and increases the uptake of glucose. Examplesof biguanides include metformin such as:

-   -   (1) 1,1-dimethylbiguanide (e.g., Metformin-DepoMed,        Metformin-Biovail Corporation, or METFORMIN GR (metformin        gastric retention polymer)); and    -   (2) metformin hydrochloride (N,N-dimethylimidodicarbonimidic        diamide monohydrochloride, also known as LA 6023, BMS 207150,        GLUCOPHAGE, or GLUCOPHAGE XR.

Additionally, anti-diabetic agents include alpha-glucosidase inhibitors,which inhibit alpha-glucosidase. Alpha-glucosidase converts fructose toglucose, thereby delaying the digestion of carbohydrates. The undigestedcarbohydrates are subsequently broken down in the gut, reducing thepost-prandial glucose peak. Examples of alpha-glucosidase inhibitorsinclude, but are not limited to:

-   -   (1) acarbose (D-glucose,        O-4,6-dideoxy-4-(((1S-(1alpha,4alpha,5beta,6alpha))-4,5,6-trihydroxy-3-(hydroxymethyl)-2-cyclohexen-1-yl)amino)-alpha-D-glucopyranosyl-(1-4)-O-alpha-D-glucopyranosyl-(1-4)-,        also known as AG-5421, Bay-g-542, BAY-g-542, GLUCOBAY, PRECOSE,        GLUCOR, PRANDASE, GLUMIDA, or ASCAROSE);    -   (2) Miglitol (3,4,5-piperidinetriol,        1-(2-hydroxyethyl)-2-(hydroxymethyl)-, (2R (2alpha, 3beta,        4alpha, 5beta))- or        (2R,3R,4R,5S)-1-(2-hydroxyethyl)-2-(hydroxymethyl-3,4,5-piperidinetriol),        also known as BAY 1099, BAY M 1099, BAY-m-1099, BAYGLITOL,        DIASTABOL, GLYSET, MIGLIBAY, MITOLBAY, PLUMAROL);    -   (3) CKD-711        (0-4-deoxy-4-((2,3-epoxy-3-hydroxymethyl-4,5,6-trihydroxycyclohexane-1-yl)amino)-alpha-b-glucopyranosyl-(1-4)-alpha-D-glucopyranosyl-(1-4)-D-glucopyranose);    -   (4) emiglitate        (4-(2-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)-1-piperidinyl)ethoxy)benzoic        acid ethyl ester, also known as BAY o 1248 or MKC 542);    -   (5) MOR 14 (3,4,5-piperidinetriol, 2-(hydroxymethyl)-1-methyl-,        (2R-(2alpha,3beta,4alpha,5beta))-, also known as        N-methyldeoxynojirimycin or N-methylmoranoline); and    -   (6) Voglibose        (3,4-dideoxy-4-((2-hydroxy-1-(hydroxymethyl)ethyl)amino)-2—C-(hydroxymethyl)-D-epi-inositol        or        D-epi-Inositol,3,4-dideoxy-4-((2-hydroxy-1-(hydroxymethyl)ethyl)amino)-2—C-(hydroxymethyl)-,        also known as A 71100, AO 128, BASEN, GLUSTAT, VOGLISTAT.

Anti-diabetic agents also include insulins such as regular orshort-acting, intermediate-acting, and long-acting insulins,non-injectable or inhaled insulin, tissue selective insulin,glucophosphokinin (D-chiroinositol), insulin analogues such as insulinmolecules with minor differences in the natural amino acid sequence andsmall molecule mimics of insulin (insulin mimetics), and endosomemodulators. Examples include, but are not limited to:

-   -   (1) Biota;    -   (2) LP 100;    -   (3) (SP-5-21)-oxobis (1-pyrrolidinecarbodithioato-S,S′)        vanadium;    -   (4) insulin aspart (human insulin (28B-L-aspartic acid) or        B28-Asp-insulin, also known as insulin X14, INA-X14, NOVORAPID,        NOVOMIX, or NOVOLOG);    -   (5) insulin detemir (Human        29B-(N-6-(1-oxotetradecyl)-L-lysine)-(1A-21A), (1B-29B)-Insulin        or NN 304);    -   (6) insulin lispro (“28B-L-lysine-29B-L-proline human insulin,        or Lys(B28), Pro(B29) human insulin analog, also known as        lys-pro insulin, LY 275585, HUMALOG, HUMALOG MIX 75/25, or        HUMALOG MIX 50/50);    -   (7) insulin glargine (human (A21-glycine, B31-arginine,        B32-arginine) insulin HOE 901, also known as LANTUS, OPTISULIN);    -   (8) Insulin Zinc Suspension, extended (Ultralente), also known        as HUMULIN U or ULTRALENTE;    -   (9) Insulin Zinc suspension (Lente), a 70% crystalline and 30%        amorphous insulin suspension, also known as LENTE ILETIN II,        HUMULIN L, or NOVOLIN L;    -   (10) HUMULIN 50/50 (50% isophane insulin and 50% insulin        injection);    -   (11) HUMULIN 70/30 (70% isophane insulin NPH and 30% insulin        injection), also known as NOVOLIN 70/30, NOVOLIN 70/30 PenFill,        NOVOLIN 70/30 Prefilled;    -   (12) insulin isophane suspension such as NPH ILETIN II, NOVOLIN        N, NOVOLIN N PenFill, NOVOLIN N Prefilled, HUMULIN N;    -   (13) regular insulin injection such as ILETIN II Regular,        NOVOLIN R, VELOSULIN BR, NOVOLIN R PenFill, NOVOLIN R Prefilled,        HUMULIN R, or Regular U-500 (Concentrated);    -   (14) ARIAD;    -   (15) LY 197535;    -   (16) L-783281; and    -   (17) TE-17411.

Anti-diabetic agents can also include insulin secretion modulators suchas:

-   -   (1) glucagon-like peptide-1 (GLP-1) and its mimetics;    -   (2) glucose-insulinotropic peptide (GIP) and its mimetics;    -   (3) exendin and its mimetics;    -   (4) dipeptidyl protease (DPP or DPPIV) inhibitors such as        -   (4a) DPP-728 or LAF 237 (2-pyrrolidinecarbonitrile,            1-(((2-((5-cyano-2-pyridinyl)amino) ethyl)amino)acetyl),            known as NVP-DPP-728, DPP-728A, LAF-237);        -   (4b) Sitagliptin, also known as Januvia;        -   (4c) Saxagliptin;        -   (4d) Linagliptin;        -   (4e) Alogliptin;        -   (4f) KRP-104;        -   (4g) AMG-222;        -   (4h) P 3298 or P32/98            (di-(3N-((2S,3S)-2-amino-3-methyl-pentanoyl)-1,3-thiazolidine)            fumarate);        -   (4i) TSL 225            (tryptophyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic            acid);        -   (4j) Valine pyrrolidide (valpyr);        -   (4k) 1-aminoalkylisoquinolinone-4-carboxylates and analogues            thereof;        -   (4l) SDZ 272-070 (1-(L-Valyl)pyrrolidine);        -   (4m) TMC-2A, TMC-2B, or TMC-2C;        -   (4n) Dipeptide nitriles (2-cyanopyrrolodides);        -   (4o) CD26 inhibitors; and        -   (4p) SDZ 274-444;    -   (5) GPR119 modulators;    -   (6) glucagon antagonists such as AY-279955; and    -   (7) amylin agonists which include, but are not limited to,        pramlintide (AC-137, Symlin, tripro-amylin or pramlintide        acetate).

Other anti-diabetic agents have also been shown to have sodium glucosecotransporter-2 (SGLT-2) inhibition activity. Examples are listed below:

-   -   (1) Dapagliflozin;    -   (2) Remogliflozin;    -   (3) TA-7284;    -   (4) LX-4211;    -   (5) BI-44847;    -   (6) BI-10773;    -   (7) ASP-1941; and    -   (8) ISIS 388626.

Well-known anti-diabetic agents include insulin, sulfonylureas,biguanides, meglitinides, AGI's (Alpha-Glucosidase Inhibitors; e.g.,Glyset), PPAR alpha agonists, and PPAR gamma agonists, and dual PPARalpha/gamma agonists.

Anti-obesity agents can be classified into several categories based uponthe mechanism of action. These agents include selective serotoninreuptake inhibitors (SSRIs), serotonin agonists, serotonin andnorepinephrine reuptake inhibitors, pancreatic lipase inhibitors,β3-adrenoreceptor agonists, NPY antagonists, melanocortin receptoragonists, leptin-targeted agents, CB1 antagonists (e.g. Rimonabant),monoamine reuptake inhibotors (e.g. Sibutramine), microsomaltriglyceride transfer protein (MTP) inhibitors and lipase inhibitors(e.g. Orlistat).

Serotonin agonist agents such as dexfenfluramine and fenfluramine werereported to cause cardiac valvular abnormalities when used at theprescribed dosage in combination with phentermine. Selective serotoninreuptake inhibitors (SSRIs) are generally used for the treatment ofdepression. These agents include fluoxetine (Prozac), paroxetine,fluvoxamine and sertraline.

Representative serotonin modulators are listed below:

-   -   (A) Selective serotonin reuptake inhibitors (SSRIs)        -   1. Citalopram (1-(3-(dimethylamino)            propyl)-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile,            also known as citalopram hydrobromide (USAN), nitalopram,            nitalapram, ZD 211, LU 10171, Lu10-171, LU 10171-B,            CIPRAMIL, SEROPRAM, CIPRAM, ELOPRAM, LUPRAM, SEPRAM,            PRISDAL, or CELEXA);        -   2. Fluoxetine (benzenepropanamine,            N-Methyl-gamma-[4-(trifluoromethyl)phenoxy]-, (±)            hydrochloride, also known as LY 110140, RENEURON, SARAFEM,            or PROZAC);        -   3. Fluvoxamine            (5-methoxy-1-(4-(trifluoromethyl)phenyl)-1-pentanone            (E)-O-(2-aminoethyl) oxime, also known as fluvoxamine            maleate (USAN), DU 23000, MK 264, SME 3110, FEVARIN,            FLOXYFRAL, LUVOX, DUMYROX, DUMIROX, FLAVOXYL, FAVERIN, or            DEPROMEL);        -   4. Indeloxazine ((+, −)-2-((indel-7-yloxy)methyl)            morpholine, also known as ideloxazine, YM 08054, CI-874,            ELEN, or NOIN);        -   5. Paroxetine hydrochloride            ((3S,4R)-3-((1,3-benzodioxol-5-yloxy)methyl)-4-(4-fluorophenyl)piperidine            hydrochloride, or piperidine,            3-((1,3-benzodioxol-5-yloxy)methyl)-4-(4-fluorophenyl)-,            (3S-trans)-, also known as FR 7051, FG-7051, BRL 29060, BRL            29060A, NNC 207051, S1211103, CASBOL, SEROXAT, AROPAX,            PAXIL, TAGONIS, FROSINOR, DEROXAT, SEREUPIN, MOTIVAN, or            PAXIL CR);        -   6. Sertraline (1-naphthalenamine,            4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-,            (1S-cis)- or            1-Naphthalenamine,4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-,            (1S-cis), also known as CP 51974, CP 51974 01, AREM IS,            BESITRAN, GLADEM, LUSTRAL, SERAD, SERLAIN, SERLIFT, TATIG,            or ZOLOFT);        -   7. Tianeptine (7-((3-chloro-6,11-dihydro-6-methyldibenzo            (c, f) (1,2) thiazepin-11-yl)amino) heptanoic acid S,            S-dioxide, also known as S 1574, or STABLON);        -   8. Centpropazine            (1-(p-propionylphenoxy)-3-(Nsup(4)-henylpiperazynyl)-propan-2-ol);        -   9. Paroxetine (GEOMATRIX drug delivery system)            (piperidine,3-((1,3-benzodioxol-5-yloxy)methyl)-4-(4-fluorophenyl)-,            (3S-trans)-, also known as paroxetine, GEOMATRIX, PAXIL CR);        -   10. Escitalopram ((1S)-1-(3-(dimethylamino)            propyl)-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran            carbonitrile, or            5-Isobenzofurancarbonitrile,1-(3-(dimethylamino)            propyl)-1-(4-fluorophenyl)-1,3-dihydro-, (S)-, also known as            escitalopram, xalate (USAN), citalopram, (S)(+)-citalopram,            LU 26042, LU 26054, Lu26-054, or CIPRALEX);        -   11. Litoxetine (4-[(2-Naphthalenyl)methoxy]piperidine, also            known as SL 810385);        -   12. (S)-Fluoxetine            ((S)—N-methyl-gamma-(4-(trifluoromethyl)phenoxy)benzenepropanamine);        -   13. Cericlamine ((+,            −)-3,4-dichloro-beta-(dimethylamino)-beta            methylbenzenepropanol, also known as JO 1017(+,−), JO            1239(−), or JO 1240(+));        -   14. Dapoxetine            ((+)-(S)—N,N-dimethyl-alpha-(2-(1-naphthyl-oxy)ethyl)benzylamine            HCl, also known as LY-210448 or LY-243917);        -   15 .6-Nitroquipazine derivatives;        -   16. Series of substituted 6-nitroquipazines (Pharmaprojects            No. 3391);        -   17. AAL 13 (2-(4-(3-chloropropyl)-1-piperazinyl) quinoline);        -   18. Depression therapy (by Vita Invest, Spain);        -   19. DUP 631 (C₁₃H₂₃N O₂S);        -   20. F14503 (by Ferrer, Spain);        -   21. Series of indolylcyclohexylamines (Pharmaprojects No.            6443, American Home Products);        -   22. LY 280253            (N-Methyl-N-[3-[4-(methylthio)phenoxy)-3-phenylpropyl]amine);        -   23. LY 285974 (by Lilly);        -   24. Omiloxetine            (Ethanone,2-((3R,4S)-3-((1,3-benzodioxol-5-yloxy)methyl)-4-(4-fluorophenyl)-1-piperidinyl)-1-(4-fluorophenyl)-,            rel-, also known as FI-4500, FI-4501, FI-4503); and        -   25. WF 31            (8-Methyl-2beta-propanoyl-3beta-(4-(1-methylethyl)-phenyl)-8-azabicyclo[3.2.1]);    -   (B) Serotonin agonists and partial agonists        -   1. Dexfenfluramine; and        -   2. Fenfluramine;    -   (C) Serotonin reuptake inhibitor with serotonin agonist activity        -   1. EMD-68843 (2-benzofurancarboxamide,            5-(4-(4-(5-cyano-1H-indol-3-yl) butyl)-1-piperazinyl)-, also            known as SB-659746-A);        -   2. OPC-14523 (2 (1H)-quinolinone,            1-(3-(4-(3-chlorophenyl)-1-piperazinyl)            propyl)-3,4-dihydro-5-methoxy);        -   3. Vilazodone            (5-{4-[4-(5-Cyano-3-indolyl)-butyl]-1-piperazinyl}-benzofuran-2-carboxamide,            also known as EMD 68843 or SB 659746A);        -   4. Series of condensed thiazoles (3-(benzo (b)            thiophen-3-yl)-5,6-dihydroimidazo            (2,1-b)thiazolemonohydrobromide dihydrate, Pharmaprojects            No. 5274, Abbott); and        -   5. VN-2222 (VN-8522, by Vita Invest, Spain).

Preferred examples of serotonin modulators include selective serotoninreuptake inhibitors such as Citalopram, Fluoxetine, Fluvoxamine,Indeloxazine, Paroxetine hydrochloride, Sertraline, Tianeptine,Centpropazine, Paroxetine, Escitalopram, and Litoxetine.

The following are also anti-obesity agents useful in the combinationtherapies of the present invention:

-   -   (A) Amylin and amylin analogs        -   1. Pramlintide            (I-Lysyl-I-cysteinyl-I-asparaginyl-I-threonyl-I-alanyl-I-threonyl-I-cysteinyl-I-alanyl-I-threonyl-I-glutaminyl-I-arginyl-I-leucyl-I-alanyl-I-asparaginyl-I-phenylalanyl-I-leucyl-I-valyl-I-histidyl-I-seryl-I-seryl-I            -asparaginyl-I-asparaginyl-I-phenylalanylglycyl-I-prolyl-I-isoleucyl-I-leucyl-I-prolyl-I-prolyl-I-threonyl-I-asparaginyl-I-valylglycyl-I-seryl-I-asparaginyl-I-threonyl-I-tyrosinamide            cyclic (2-7)-disulfide, also known as pramlintide acetate,            AC 137, ACO 137, AC 0137, SYMLIN, Tripro-amylin, or            NORMYLIN);        -   2. Amylin agonists;        -   3. ACO 253 (AC 253, GG 747, GR 1150747A, or ANTAM);    -   (B) Ciliary neurotrophic factors (CNTF)        -   1. AXOKINE;        -   2. PEG-AXOKINE;        -   3. Peptide mimic of ciliary neurotrophic factor (CNTF mimic,            also known as MYELOS);        -   4. Ciliary neurotrophic factor (CNTF by Fidia, Italy);    -   (C) Glucagon-like peptide-1        -   1. AC-2993 (also known as exendin-4, AC-2993 LAR, Medisord            Exendin, AC-2993, Medisorb, or extendin-4, Amylin);        -   2. Exendin 4            (His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-V-al-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-amide,            also known as AC 2993, AC 2993 LAR, Medisord Exendin, or            AC-2993, Medisorb);        -   3. GLP-1 (Glucagon-like peptide-17-36 amide);        -   4. Glucagon-like peptide-1 oral transmucosal formulation;        -   5. Exendin 3            (His-Ser-Asp-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-V-al-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-amide);    -   (D) Leptin & leptin mimetics        -   1. Leptin (2nd-generation);        -   2. Leptin agonists;        -   3. Leptin expression modulators;        -   4. Leptin signalling pathway modulators;        -   5. Leptin modulator;        -   6. Leptin (by IC Innovations, UK);        -   7. Leptin receptor, Monoclonal antibodies;        -   8. Recombinant native leptin;        -   9. LY-355101;        -   10. Leptin, Amylin;    -   (E) Melanocortin receptor agonist (MC4)        -   1. HP-228 (Glycinamide,            N-acetyl-L-norleucyl-L-glutaminyl-L-histidyl-D-phenylalanyl-L-arginyl-D-tryptophyl-);        -   2. Melanocortin-4 receptor agonist (by Palatin, USA);        -   3. Melanocortin 4 agonist (by Pharmacopeia, Roche);        -   4. MC-4 agonists (by Millennium, Chiron);        -   5. Melanocortin-4 agonist (by Melacure Therapeutics,            Sweden);        -   6. Melanocortin receptor modulators (Pharmaprojects No.            5224, Neurocrine Biosciences, US);        -   7. Pharmaprojects No. 5967, Trega/Novartis;    -   (F) NPY antagonists        -   1. AXC 0216;        -   2. AXC 1829;        -   3. SA-0204 (Neuropeptide γ antagonist, Apoptosis stimulator,            Lipid metabolism modulator);        -   4. Alpha-trinositol (D-myo-Inositol, 1,2,6-tris (dihydrogen            phosphate), also known as PP-56);        -   5. H 40922 (H 409/22);        -   6. BMS-192548 (1,11            (4H,5H)-naphthacenedione,2-acetyl-4-a,12a-dihydro-3,4-a,10,12,12a-pentahydroxy-8-methoxy-,            TAN 1612 isomer);        -   7. Alanex            (1,4-bis{(4-amino-6-methoxyphenylamino-1,2-dihydro-1,3,5-triazin-2-yl)-4-phenoxymethyl}benzene,            Neuropeptide Y derivatives);        -   8. PD-160170            (6-(2-isopropyl-benzenesulfonyl)-5-nitro-quinolin-8-ylamine);        -   9. 2,4-Diaminopyridine derivatives            (6-(5-ethyl-1,3,4-thiadiazol-2-ylthiomethyl)-4-morpholino-2-(3-(2-propenyloxycarbonylamino)            benzylamino) pyridine, Pharmaprojects No. 5618,            Banyu/Merck);        -   10. Arpromidine analogs;        -   11. Neuropeptide γ antagonist (Pharmaprojects No. 4990,            Pfizer);        -   12.4 Methyl substituted benzimidazoles (NPY-1 antagonist,            NPY-2 antagonist);        -   13. LY-366337 (Neuropeptide Y1 antagonist);        -   14. S-2501, S-25579, S-25584, S-25585, S-19528, S-34354 (all            Neuropeptide Y1/5 antagonists);        -   15. Neuropeptide γ antagonist (subtypes 1 and 5) and Galanin            receptor antagonist (Pharmaprojects No. 4897, Bristol-Myers            Squibb);        -   16. Benzylamine derivatives            (1-arylpiperazinyl-1-alkyloxyphenyl-4-alkylcycloalkanes);        -   17. J-104870 (Neuropeptide Y1 antagonist, Appetite            suppressant);        -   18. LY-357897 (Neuropeptide Y1 antagonist);        -   19. Neuropeptide Y1 antagonist (Pfizer/Neurogen);        -   20.5R-120107A (Neuropeptide Y1 antagonist);        -   21. BIBO-3304            ((R)—N-((4-(aminocarbonylaminomethyl)-phenyl)methyl)-N-2-(diphenylacetyl)-argininamide            trifluoroacetate);        -   22. BIBP 3226            ((R)—N-(4-((aminoiminomethyl)amino)-1-((((4-hydroxyphenyl)methyl)amino)            carbonyl) butyl)-alpha-phenylbenzeneacetamide, or            benzeneacetamide,            N-((1R)-4-((aminoiminomethyl)amino)-1-((((4-hydroxyphenyl)methyl)amino)            carbonyl) butyl)-alpha-phenyl-);        -   23. SR 120819A (benzenepropanamide,            N—(1-((4-((((4-((dimethylamino)            methyl)cyclohexyl)methyl)amino)            iminomethyl)phenyl)methyl)-2-oxo-2-(1-pyrrolidinyl)ethyl)-alpha-((2-naphthalenylsulfonyl)amino)-,            (alphaR-(N(R*(cis)), alphaR*))-)        -   24. NGD-95-1 (CP-422935, NGD 951);        -   25. Compounds with benzazepine nuclei (Neuropeptide Y1            antagonist);        -   26. Neuropeptide Y1 antagonist (by Yamanouchi            Pharmaceutical);        -   27. GI-264879A (Neuropeptide Y1 antagonist);        -   28. GW-1229 ([2′,4],[2,4′]homodimer of            Ile-Glu-Pro-Dpr-Tyr-Arg-Leu-Arg-Tyr-CONH2, where Dpr is            diaminopropionic acid, also known as 1229U91, MN-24,            GR-231118);        -   29. BIIE-0246 (Cyclopentaneacetamide,            N-[(1S)-4-[(aminoiminomethyl)amino]-1-[[[2-(3,5-dioxo-1,2-diphenyl-1,2,4-triazolidin-4-yl)ethyl]amino]carbonyl]butyl]-1-[2-[4-(6,11-dihydro-6-oxo-5H-dibenz[b,e]azepin-11-yl)-1-piperazinyl]-2-oxoethyl]-);        -   30. Neuropeptide Y2 antagonist (by Neurogen, USA);        -   31. Amide derivatives (Neuropeptide Y5 antagonist);        -   32. Neuropeptide Y agonist and antagonist-subtypes 1 and 5            (Schering-Plough);        -   33.            N-(sulfonamido)alkyl-[3a,4,5,9b-tetrahydro-1H-benzo[e]indol-2-yl]amine            (RWJPR1);        -   34. Neuropeptide Y5 antagonist (by Novartis);        -   35. Neuropeptide Y5 antagonist (by Pfizer/Neurogen);        -   36. Pyrrolo[3,2-d]pyrimidine based neuropeptide Y5            antagonists;        -   37. CGP-71683 (Pharmaprojects No. 5651, CGP-71683A);        -   38. Neuropeptide Y5 agonist/antagonist (Pharmaprojects No.            5664, Bayer);    -   (G) Histamine H3 receptor antagonists        -   1. GT-2331            (3-((1R,2R)-2-(5,5-dimethyl-1-hexynyl)cyclopropyl)-1H-imidazole,            also known as PERCEPTIN);        -   2. Ciproxifan (Cyclopropyl-(4-(3-1H-imidazol-4-yl)            propyloxy)phenyl)methanone, also known as BP 2359 or            Compound 359);        -   3. Compound 421 (imidazoylpropanol derivative, INSERM            (France)/Bioprojet);        -   4. FUB 181 (3-(4-chlorophenyl) propyl-3-(1H-imidazol-4-yl)            propyl ether);        -   5. GR 175737            (3-((4-chlorophenyl)methyl)-5-(2-(1H-imidazol-4-yl)ethyl)-1,2-oxadiazole);        -   6. GT 2227 (4-(6-cyclohexyl-3(Z)-hexenyl) imidazole            maleate);        -   7. GT 2394            ((1R,2R)-(trans-2-Imidazol-4-ylcyclopropyl)-(cyclohexylmethoxy)            carboxamide);        -   8. GT-2016 (piperidine,            1-(5-cyclohexyl-1-oxopentyl)-4-(1H-imidazol-4-yl)-);        -   9. Imoproxifan (1-(4-(3-(1H-imidazol-4-yl)            propoxy)phenyl)ethan-1-one oxime);        -   10. Impentamine (by Berlin Free University);        -   11. Abbott Laboratories H3 antagonist for Attention deficit            Hyperactivity Disorder (ADHD);        -   12. Gliatech (USA) H3 antagonist for eating disorder;        -   13. Series of novel carbamates as derivatives of            3-(1H-imidazol-4-yl)propanol with an N-alkyl chain;        -   14. Series of analogs with a neutral linker leading to            4-(1H-imidazol-4-ylmethyl)benzene;        -   15. Urea,            N-4-(1H-imidazol-4-ylmethyl)phenylmethyl-N′-(3,5-dichlorophenyl)-,            monohydrochloride;        -   16. Sch-50971 (1H-imidazole,            4-[(3R,4R)-4-methyl-3-pyrrolidinyl]-);        -   17. Thioperamide            (N-cyclohexyl-4-(1H-imidazol-4-yl)-1-piperidinecarbothioamide,            also known as MR 12842);        -   18. UCL-1283 (by University College London);        -   19. UCL-1390 (4-(3-(1H-imidazol-4-yl) propoxy)benzonitrile);        -   20. UCL-1409 ((phenoxyalkyl)imidazoles);        -   21. UCL-1972 (by University College London);        -   22. Verongamine (benzenepropanamide,            3-bromo-.alpha.-(hydroxyimino)-N-[2-(1H-imidazol-4-yl)ethyl]-4-methoxy-,            (E)-);        -   23. VUF-9153 (Carbamimidothioic acid,            [(4-chlorophenyl)methyl]-, 3-(1H-imidazol-4-yl)propyl ester,            also known as Clobenpropit);    -   (H) Pancreatic lipase inhibitors        -   1. Orlistat (L-Leucine, N-formyl-,            1-((3-hexyl-4-oxo-2-oxetanyl)methyl) dodecyl ester,            (2S-(2alpha (R*),3beta))-, or N-formyl-L-leucine (2S-(2alpha            (R*),3beta))-1-((3-hexyl-4-oxo-2-oxetanyl)methyl) dodecyl            ester, also known as Orlipastat, RO 180647,            Tetrahydrolipstatin (THL), XENICAL, or ZENICAL);        -   2. ATL 962 (also known as AZM 119 or Alizyme);        -   3. GelTex (Anti-obesity therapeutics);        -   4. AZM-131 (by Yakurigaku Chuo Kenkyusho/Institute of Food            Research);        -   5. RED 103004 (XiMed Group (United Kingdom)/BioClin);    -   (I) Alpha melanocyte stimulating hormone analogues        -   1. Melanotan II            (acetyl-norleucyl-aspartyl-histidyl-D-phenylalanyl-arginyl-tryptophyl-lysinamide            C-4,2-N-6.7-lactam, also known as MT II);        -   2. MBU-23, MBU-23, MBU-24, MBU-27, MBU-28 and MBU-29 (all            described in WO 1998027113);        -   3. MSH fusion toxin (also known as DAB389MSH, antimelanoma,            chimaera);        -   4. SHU-9119 (L-Lysinamide,            N-acetyl-L-norleucyl-L-.alpha.-aspartyl-L-histidyl-3-(2-naphthalenyl)-D-alanyl-L-arginyl-L-tryptophyl-,            (2.fwdarw.7)-lactam, also known as MBX 36);        -   5. SHU-9005 (a substituted derivative of alpha-MSH);        -   6. ZYC-200 (alpha-MSH, Schepens/ZYCOS with BIOTOPE            expression cassette system);    -   (J) Mixed serotonin reuptake inhibitor with serotonin or alpha        adrenergic antagonist activity        -   1. Nefazodone            (2-(3-(4-(3-chlorophenyl)-1-piperazinyl)propyl)-5-ethyl-2,4-dihydro-4-(2-phenoxyethyl)-3H-1,2,4-triazol-3-one,            also known as MJ 13754, MS13754, BMY 13754, BMY 137541,            SERZONE, DUTONIN, RESERIL, NEFADAR, NIFEREL, MENFAZONA,            RULIVAN, DEPREFAX, or SERZONIL);        -   2. YM 992 ((S)-2-(((7-fluoro-2,3-dihydro-1H-inden-4-yl)            oxy)methyl) morpholine hydrochloride, or            (S)-2-(((7-fluoro-2,3-dihydro-1H-inden-4-yl) oxy)methyl)            morpholine hydrochloride, also known as YM 35992);        -   3. A 80426            ((R)—N-methyl-N-((1,2,3,4-tetrahydro-5-methoxy-1-naphthalenyl)methyl)-6-benzofuranethanamine);        -   4. 5-HT1A antagonist (by Vita-Invest, Spain);        -   5. Nefazodone metabolite (by Sepracor, USA);        -   6. Serotonin reuptake inhibitors/serotonin 1A antagonists            (Wyeth-Ayerst);    -   (K) Appetite-suppressants acting through adrenergic mechanisms        -   1. benzphetamine;        -   2. phenmetrazine;        -   3. phentermine;        -   4. diethylpropion;        -   5. mazindol;        -   6. sibutramine;        -   7. phenylpropanolamine;        -   8. ephedrine;    -   (L) Mixed serotonin & dopamine reuptake inhibitors        -   1. BL-1834 (1-propanamine, 3-dibenz (b, e)            oxepin-11(6H)-ylidene-N,N-dimethyl);        -   2. NS-2389 or NS-2347 (GW-650250A, GW 650250);        -   3. (R)-Sibutramine;        -   4. NS-2359 (by NeuroSearch, Denmark);        -   5. RTI-112 or RTI-113 or RTI-177 (8-Azabicyclo (3.2.1)            octane-2-carboxylic            acid,3-(4-chloro-3-methylphenyl)-8-methyl-, methyl ester,            hydrochloride, (1R,2S,3S,5S));        -   6. BSF-74681(Abbott);        -   7. Hyperforin trimethoxybenzoate (IDN-5491);    -   (M) Mixed serotonin reuptake inhibitors and dopamine antagonist        -   1. SLV-310 (Solvay, Belgium);        -   2. EMD 86006            (3-(2-(3-(4-fluorophenyl)benzylamino)ethoxy)benzonitrile);        -   3. SLV 301 (by Solvay);    -   (N) Norepinephrine & serotonin reuptake inhibitors (NSR1)        -   1. Milnacipran (Cyclopropanecarboxamide,            2-(aminomethyl)-N,N-diethyl-1-phenyl-, cis-(+/−)-, or            (±)-cis-2-(Aminomethyl)-N-diethyl-1-phenyl cyclopropane            carboxamide hydrochloride, also known as F-2207, F-2641,            TN-912, DALCIPRAN, IXEL, MIDACIPRAN, MIDALCIPRAN,            MILNACIPRAN SR, TOLEDOMIN);        -   2. Tramadol, Purdue (cyclohexanol, 2-((dimethylamino)            methyl)-1-(3-methoxyphenyl)-, cis-(+/−), also known as            TRAMADOL, Tramadol, CR, or Toray);        -   3. Milnacipran (drug delivery system, sustained release);        -   4. Duloxetine            ((S)—N-methyl-gamma-(1-naphthalenyloxy)-2-thiophenepropanamine,            or            (+)-(S)—N-Methyl-gamma-(1-naphthyloxy)-2-thiophene-propylamine            hydrochloride, also known as LY 248686, duloxetine oxalate,            LY-223332, LY-223743, LY-223994, LY-227750, LY-227942,            LY-228993, LY-248686, LY-264452, LY-264453, LY-267826;        -   5. Naltrexone+tramadol            (morphinan-6-one,17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxy-,            (5alpha)-, mixt withcyclohexanol,            2-((dimethylamino)methyl)-1-(3-methoxyphenyl)-, cis-(+/−)-,            also known as PTI-601, tramadol+naltrexone, Pain T);        -   6. (S) sibutramine            ((S)-1-(4-chlorophenyl)-N,N-dimethyl-alpha-(2-methylpropyl)cyclobutanemethanamine);        -   7. Tramadol, Labopharm (cyclohexanol, 2-((dimethylamino)            methyl)-1-(3-methoxyphenyl)-, cis-(+/−), also known as            tramadol, Contramid);        -   8. F 98214TA (by FAES, Spain);        -   9. S 33005            ((+1-(1-Dimethylaminomethyl-5-methoxybenzocyclobutan-1-yl)cyclopentanol);        -   10. Tacrine analogues, SIDR;    -   (O) Serotonin, norepinephrine and dopamine reuptake inhibitors        -   1. Sibutramine            (cyclobutanemethanamine,1-(4-chlorophenyl)-N,N-dimethyl-alpha-(2-methylpropyl)-,            or            1-(4-chlorophenyl)-N,N-dimethyl-alpha-(2-methylpropyl)cyclobutanemethanamine            hydrochloride monohydrate, also known as Sibutramine            hydrochloride monohydrate, BTS-54354, BTS-54505, BTS-54524,            KES-524, MERIDIA, REDUCTIL, RADUCTIL, REDUCTASE, PLENTY,            ECTIVA);        -   2. Venlafaxine (cyclohexanol,            1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl], also known            as WY 45030, WY 45651, WY 45655, DOBUPAL, EFECTIN, EFEXOR,            EFFEXOR, ELAFAX, VANDRAL, TREVILOR);        -   3. Venlafaxine XR (cyclohexanol,            1-(2-(dimethylamino)-1-(4-methoxyphenyl)ethyl)-,            hydrochloride, also known as EFFEXOR XR,I EFFEXOR ER,            EFFEXOR XL, EFFEXOR LP, DOBUPAL RETARD, VANDRAL RETARD,            EFFEXOR-EXEL 75, EFEXOR XR, EFEXOR DEPOT, ELAFAX XR);        -   4. Venlafaxine (drug delivery system, OROS oral controlled            release, also known as venlafaxine, OROS, or EFEXOR XR);        -   5. (+)-Desmethylsibutramine (also known as DDMS,            Didesmethylsibutramine-Sepracor);        -   6. BTS-74398            (1-[1-(3,4-Dichlorophenyl)cyclobutyl]-2-(3-dimethylaminopropylthio)ethanone,            Abbott Pharmaprojects No. 6247);        -   7. Desmethylvenlafaxine (by Sepracor);    -   (P) Appetite-suppressant agents acting through dopamine        mechanisms        -   1. Apomorphine;    -   (Q) Selective norepinephrine (noradrenaline) reuptake inhibitors        -   1. Reboxetine            ((2S)-rel-2-((R)-(2-ethoxyphenoxy)phenylmethyl) morpholine,            or morpholine, 2-[(2-ethoxyphenoxy)phenylmethyl]-, (R,S)—,            methanesulfonate, also known as reboxetine mesylate (USAN),            FCE 20124, FCE 21684, PNU 155950E, EDRONAX, PROLIFT, VESTRA,            IRENON, NOREBOX);        -   2. Tomoxetine            ((gamma.R)—N-methyl-gamma-(2-methylphenoxy)benzenepropanamine,            or (−)-N-Methyl-3-phenyl-3-(o-tolyloxy)-propylamine            hydrochloride, also known as LY 139603, LY 135252, LY            139602);        -   3. Hydroxynortriptyline            ((E)-10-11-dihydro-5-(3-(methylamino)            propylidene)-5H-dibenzo-(a, d) cyclohepten-10-ol);        -   4. LY 368975            ((R)—N-Methyl-3-[2-(methylsulfanyl)phenoxy]-3-phenyl-propylamine            hydrochloroide);    -   (R) Combined norepinephrine and dopamine reuptake inhibitors        -   1. Bupropion            (1-(3-chlorophenyl)-2-((1,1-dimethylethyl)amino)-1-propanone,            also known as bupropion hydrochloride (USAN), bupropin,            amfebutamone, BW 323U, WELLBUTRIN, QUOMEM, or ZYBAN);        -   2. GW 320659            ((2S-(2alpha,3alpha,5alpha))-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol            hydrochloride, also known as 1555, 1555U88, BW 1555U88);        -   3. Hydroxy bupropion (also known as bupropion, R-, or            R-bupropion);        -   4. (−) Didesmethylsibutramine (also known as            (S)-didesmethylsibutramine, desmethylsibutramine, (−)-DDMS            or MERIDIA (urogenital));    -   (S) Mixed norepinephrine reuptake inhibitor and other        neurotransmitter antagonists        -   1. Zotepine (2-((8-chlorodibenzo (b, f)thiepin-10-yl)            oxy)-N,N-dimethylethylamine, also known as LODOPIN,            NIPOLEPT, ZOLEPTIL, ZOPITE, SETOUS, MAJORPIN);        -   2. MCI-225            (4-(2-fluorophenyl)-2-methyl-6-(piperazin-1-yl)-3a,7a-dihydrothieno            (2,3-d) pyrimidine, or            4-(2-Fluorophenyl)-6-methyl-2-piperazinothieno[2,3-d]pyrimidine            hydrochloride hydrate);        -   3. A 75200 ((R*, R*)-(+,            −)-3-phenyl-1-((6,7,8,9-tetrahydronaphtho            (1,2-d)-1,3-dioxol-6-yl)methyl)pyrrolidine);    -   (T) Combined serotonin reuptake inhibitors and sigma receptor        antagonists        -   1. E-5296 (by Esteve, Spain);        -   2. E-6276 (by Esteve, Spain);        -   3. E-5842 (pyridine,            4-(4-fluorophenyl)-1,2,3,6-tetrahydro-1-(4-(1H-1,2,4-triazol-1-yl)            butyl)-, 2-hydroxy-1,2,3-propanetricarboxylate (1:1));        -   4. E 5826 (citrate salt of E-5842);    -   (U) Other neurotransmitter modulators with serotonin or        norepinephrine uptake inhibitor activity        -   1. Pirlindole (1H-pyrazino (3,2,1-jk) carbazole,            2,3,3a,4,5,6-hexahydro-8-methyl-, also known as CAS-125,            Pyrazidol, pirazidol, LIFRIL, IMPLEMENTOR);        -   2. NS-2330 (by NeuroSearch, Denmark);        -   3. VAN-H36 (by Vita-Invest, Spain);        -   4. UR 1827            (2-(1-Benzylpiperidin-4-yl)-1-[4-(5-methylpyrimidin-4-ylamino)phenyl]-1-ethanone);    -   (V) C-75 (Fatty acid synthase inhibitor)    -   (W) S 15261 (L-4-(2-(2-(9-Fluorenyl)acetamido) ethyl)benzoic        acid 2-(2-methoxy-2-(3-(trifluoromethyl)phenyl)ethylamino) ethyl        ester)    -   (X) S 100B (Neurotrophic factor)    -   (Y) Stimulators of uncoupling protein function    -   (Z) Cholecystokinin agonists    -   (AA) Androgens        -   1. dehydroepiandrosterone;        -   2. dehydroepiandrosterone derivatives (such as            etiocholandione);    -   (BB) Testosterone    -   (CC) Anabolic steroids (eg, oxandrolone)    -   (DD) Steroidal hormones    -   (EE) Amylase inhibitors    -   (FF) Enterostatin agonists/mimetics    -   (GG) Orexin/hypocretin antagonists    -   (HH) Urocortin antagonists    -   (II) Bombesin agonists    -   (JJ) Modulators of protein kinase A    -   (KK) Corticotropin-releasing factor mimetics    -   (LL) Cocaine- and amphetamine-regulated transcript mimetics    -   (MM) Calcitonin-gene related peptide mimetics    -   (NN) Nizatidine (Axid).

Examples of lipid lowering agents include bile acid sequestrants, fibricacid derivatives, nicotinic acid, and HMGCoA reductase inhibitors.Specific examples include statins such as LIPITOR®, ZOCOR®, PRAVACHOL®,LESCOL®, CRESTOR®, and MEVACOR®, and pitavastatin (nisvastatin) (Nissan,Kowa Kogyo, Sankyo, Novartis) and extended release forms thereof, suchas ADX-159 (extended release lovastatin), as well as Colestid,Locholest, Questran, Atromid, Lopid, and Tricor.

Examples of blood pressure lowering agents include anti-hypertensiveagents, such as angiotensin-converting enzyme (ACE) inhibitors(Accupril, Altace, Captopril, Lotensin, Mavik, Monopril, Prinivil,Univasc, Vasotec, and Zestril), adrenergic blockers (such as Cardura,Dibenzyline, Hylorel, Hytrin, Minipress, and Minizide) alpha/betaadrenergic blockers (such as Coreg, Normodyne, and Trandate), calciumchannel blockers (such as Adalat, Calan, Cardene, Cardizem, Covera-HS,Dilacor, DynaCirc, Isoptin, Nimotop, Norvace, Plendil, Procardia,Procardia XL, Sula, Tiazac, Vascor, and Verelan), diuretics, angiotensinII receptor antagonists (such as Atacand, Avapro, Cozaar, and Diovan),beta adrenergic blockers (such as Betapace, Blocadren, Brevibloc,Cartrol, Inderal, Kerlone, Lavatol, Lopressor, Sectral, Tenormin,Toprol-XL, and Zebeta), vasodilators (such as Deponit, Dilatrate, SR,Imdur, Ismo, Isordil, Isordil Titradose, Monoket, Nitro-Bid, Nitro-Dur,Nitrolingual Spray, Nitrostat, and Sorbitrate), and combinations thereof(such as Lexxel, Lotrel, Tarka, Teczem, Lotensin HCT, Prinzide,Uniretic, Vaseretic, Zestoretic).

F) Biological Example

TR-FRET Assay

Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET)experiments were performed to examine the functional response of ERR1(also known as ERR-α or ERR-1) ligands. The TR-FRET assay describedherein relied on the conformation of ERR1 for binding to a co-activatorpeptide: when a test compound binds to ERR1 and alters its conformation,it can disrupt the binding of the co-activator peptide. The componentsof this homogeneous secondary assay included: the ⁶His-tagged-ERR1LBD, aGST-labeled-hSRC2 co-activator polypeptide and a fluorescentdonor/acceptor pair from CIS bio international htrf/bioassays (Bedford,Mass.) using both an α-GST Europium Cryptate (Eu) label and anα⁶His-XL665 (allophycocyanin) fluorophore.

For TR-FRET measurements, the reaction was buffered in 25 mM Tris pH 8,2.5 mM Hepes, 20 mM KCl, 1 mM DTT, and 0.05 mg/mL BSA (-lipids). Thefinal concentrations of reagents were 6 nM of ERR1LBD, 6 nM GST-SRC-2peptide, 30 nM Eu cryptate, and 7.5 nM XL665. Reactions were allowed toreach equilibrium at 25° C. for 4-18 hours before collecting data on theAnalyst from LJL Biosystems (Molecular Devices Sunnyvale, Calif.). As atime-resolved method, the samples were excited at 340 nM and emissionwas collected for 1 ms at both 615 and 665 nm with delays of 400 and 75μs, respectively. Dose response curves were fitted using a hyperbolicequation and the data reported is the average of 3 independentexperiments.

Compounds listed in Tables II below were tested in the above assay, andthey are all active modulators of ERR1.

TABLE II TR-FRET data COMPOUND # EC₅₀ TR-FRET (μM) 1 0.0101 2 0.0072 30.0210 4 0.0920 5 0.0420 6 0.0090 7 0.0380 8 0.0070 9 0.0575 10 0.199011 0.0570 12 0.0046 13 0.0047 14 0.0680 15 0.5300 16 0.4500 17 >4.0003718 >4.00037 19 0.3500 20 0.3000 21 0.0030 22 0.0114 23 0.0104 24 0.520025 0.0680 26 0.0048 27 0.0110 28 0.0590 29 0.0380 30 0.0230 31 0.0046 320.0100 33 0.0044 34 0.0075 35 0.0143 36 0.0054 37 0.0053 38 0.0090 390.0032 40 0.0080 41 0.0150 42 0.0042 43 0.0110 44 0.0032 45 0.0340 460.0270 47 0.0082 48 0.0143 49 0.0060 50 0.0078 51 0.0090 52 0.0045 530.0130 54 0.0131 55 0.0610 56 0.0157 57 0.0121 58 0.0420 59 0.0230 600.0197 61 0.0196 62 0.0173 63 0.0540 64 0.0250 65 0.0170 66 0.0249 670.0210 68 0.0096 69 0.0260 70 0.0110 71 0.0164 72 0.0133 73 0.1725 740.0562 75 0.0734 76 0.0183 77 0.0587 78 0.0045 79 0.0090 80 0.0057 810.0688 82 0.0076 83 0.0150 84 0.0390 85 0.0086 86 0.0200 87 0.0150 880.0130 89 0.0047 90 0.0034 91 0.0087 92 0.0490 93 0.0144 94 0.0260 950.0110 96 0.0640 97 0.0290 98 0.0150 99 0.0028 100 0.0140 101 0.0214 1020.0220 103 0.0122 104 0.0182 105 0.0409 106 0.0210 107 0.2230 108 0.0302109 0.0360 110 0.0186 111 0.0069 112 0.0290 113 0.0140 114 0.0130 1150.0084 116 0.0110 117 0.0083 118 0.0073 119 0.0140 120 0.0270 121 0.0253122 0.0418 123 0.0050 124 0.0090 125 0.0100 126 0.0240 127 0.0290 1280.0320 129 0.0280 130 0.0320 131 0.0078 132 0.0107 133 0.0041 134 0.0050135 0.0520 136 0.0340 137 0.0140 138 0.0190 139 0.0160 140 0.0190 1410.0370 142 0.0200 143 0.0560 144 0.0140 145 0.0210 146 0.0140 147 0.0110148 0.0330 149 0.0550 150 0.0480 151 0.0257 152 0.0240 153 0.0440 1540.0262 155 0.0340 156 0.0580 157 0.0350 158 0.0320 159 0.0360 160 0.0220161 0.0248 162 0.0270 163 0.0260 164 0.0120 165 0.0180 166 0.0190 1670.0160 168 0.0090 169 0.2250 170 0.0300 171 0.0380 172 0.0140 173 0.0710174 0.0581 175 0.0050 176 0.1387 177 0.0550 178 0.0520 179 0.0170 1800.0210 181 0.0160 182 0.0108 183 0.0049 184 0.0030 185 0.0030 186 0.0050187 0.0127 188 0.0197 189 0.0240 190 0.0530 191 0.0036 192 0.0160 1930.0110 194 0.0235 195 0.0200 196 0.0160 197 0.0290 198 0.0150 199 0.0110200 0.0130 201 0.0470 202 0.0597 203 0.0388 204 0.0420 205 0.0300 2060.0280 207 0.0380 208 0.0060 209 0.0060 210 0.0248 211 0.0310 212 0.0200213 0.0210 214 0.0080 215 0.0480 216 0.0150 217 0.0270 218 0.0360 2190.0230 220 0.0214 221 0.0070 222 0.0200 223 0.0134 224 0.0700 225 0.0180226 0.0080 227 0.0150 228 0.0260 229 0.5800 230 0.1340 231 0.4900 2320.7951 233 0.1270 234 0.0160 235 0.0050 236 0.0030 237 0.0060 238 0.0110239 0.0180 240 0.0090 241 0.0040 242 0.0300 243 0.0380 244 0.1100 2450.2350 246 0.2300 247 0.0410 248 0.0140 249 0.0040 250 0.1900 251 0.0040252 0.1900 253 0.0050 254 0.0065 255 0.0280 256 0.0490 257 0.0960 2580.0300 259 0.0300 260 0.2900 261 0.0200 262 0.0640 263 0.0420 264 0.0470265 0.0380 266 0.0240 267 0.0430 268 0.0150 269 0.0150 270 0.0080 2710.0090 272 0.0350 273 0.0060 274 0.0080 275 0.0110 276 0.0240 277 0.0090278 0.0170 279 0.0110 280 0.0030 281 0.59 282 >4.001 283 0.013Zucker fa/fa Rat Model Assay

Zucker fa/fa is a monogenic model of frank diabetes due to a mutation onthe fa gene truncating the leptin receptor and preventing itsinteraction with its peptide hormone. This mutation results in ahyperphagic phenotype and the rodent develops obesity, hyperlipidemia,fasting hyperglycemia and insulin resistance. Zucker fa/fa male ratswere received at four weeks of age and allowed to acclimate for oneweek. At five weeks of age the animals were single housed in cages in atemperature-controlled room with 12-hour light/dark cycle. The rats wereallowed ad libitum access to water and food and throughout the studywere maintained on a Purina 5008 diet. Animals were sorted basedprimarily on fed insulin levels and circulating triglycerides. Animalswere dosed orally once a day in the morning for 4 days. The vehicle usedwas either 20% HPβCD (Hydroxypropyl Beta Cyclodextrin) or 15% VitaminE/30% PEG-400 (Polyethylene Glycol 400). Fed insulin and triglycerideswere measured using blood collected from the tail vein at day 5. Serumplasma samples were prepared by centrifugation in EDTA(Ethylenediaminetetraacetic acid) containing tubes, transferred into 96well plates and stored at −80° C. Results are summarized in Table III.

TABLE III Zucker fa/fa Rat Model Data % Lowering % Lowering FedTriglyceride COMPOUND # Fed Insulin Levels Levels 1 58 37 35 45 20 39 5835 40 75 60 52 86 55 54 60 27 56 70 68 62 48 36 64 46 51 71 37 25 72 6257 98 51 22 125 30 N/A 139 82 58 140 59 67 141 49 76 142 63 55 186 75 56188 81 59 197 27 2 198 35 21 213 42 30 223 77 85

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

1. A compound of Formula (I)

wherein X is —CH— or N; R₁ is C₁₋₃alkyl, halo, cycloalkyl, and—C(O)—C₁₋₄alkyl; wherein said C₁₋₃alkyl may be substituted with halo; R₂is —H, halo, cyano, C₁₋₃alkyl, C₂₋₃alkenyl, C₁₋₄alkoxy, hydroxyl,cycloalkyl, —C(O)O—C₁₋₄alkyl, —C(O)NH₂, —OS(O₂)—C₁₋₄alkyl,—O—C₁₋₄alkyl—O—C₁₋₄alkyl, heterocyclyl, heteroaryl, or —S(O₂)—C₁₋₄alkyl;wherein said C₁₋₃alkyl may be substituted with halo or hydroxyl; R₃ is—H, halo, cyano, or C₁₋₃alkyl; and

is a 4 to 9 membered heterocyclyl bonded to the rest of the moleculethrough a ring nitrogen atom and optionally containing 1-2 heteroatomsin addition to said ring nitrogen atom, wherein the optional 1-2additional heteroatoms are independently selected from the groupconsisting of N, O and S; wherein said 4 to 9 membered heterocyclyl maybe substituted with C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, halo, oxo,cyano, hydroxyl, —OR⁵, —O—C₁₋₄alkyl-C(O)OR⁵, cycloalkyl, heteroaryl,heterocyclyl, —C(O)OR⁵, —C(O)N(R⁵)(R⁶), —C(O)N(R⁵)(OR⁶), —C(O)R⁵,—C(O)—C₁₋₄alkyl-N(R⁵)(R⁶), —C(O)—C₁₋₄alkyl—O—C₁₋₄alkyl,—C(O)N(R⁵)—S(O)₂(R⁶), —C(O)N(R⁵)—OR⁶, —C(O)N(R⁵)S(O)₂N(R⁵)(R⁶),—C(O)N(R⁵)—C₁₋₄alkyl-C(O)OR⁶, —N(R⁵)(R⁶), —N(R⁵)—C₁₋₄alkyl—OR⁶,—N(R⁵)C(O)R⁶, —N(R⁵)C(O)OR⁶, —N(R⁵)S(O)₂R⁶, —N(R⁵)C(O)—NH(R⁶),—N(R⁵)—C₁₋₄alkyl-C(O)—NH(R⁶), —SR⁵, —S(O)₂R⁵, or —S(O)₂—N(R⁵)(R⁶);wherein said C₁₋₄alkyl may be substituted with —OH, —O—C₁₋₄alkyl,—C(O)OR⁵, —C(O)N(R⁵)(R⁶), —N(R⁵)(R⁶), —N(R⁵)C(O)OR⁶, heterocyclyl,heteroaryl, cycloalkyl, or halo; wherein said heteroaryl may besubstituted with C₁₋₄alkyl, halo, cyano, —CF₃, alkoxy or hydroxyl;wherein said heterocyclyl may be substituted with C₁₋₄alkyl, oxo, halo,amino, alkoxy, or hydroxyl; wherein said C₂₋₄alkenyl and saidC₂₋₄alkynyl may be independently substituted with oxo, heterocyclyl,hydroxyl, or halo; wherein R⁵ and R⁶ are each independently —H,C₁₋₄alkyl, cycloalkyl, or heterocyclyl, wherein said C₁₋₄alkyl may besubstituted with halo or hydroxyl; or alternatively R⁵ and R⁶ are linkedtogether to form a 5-7 membered ring; or an optical isomer, enantiomer,diastereomer, cis-trans isomer, racemate, or pharmaceutically acceptablesalt thereof.
 2. The compound of claim 1 wherein X is —CH—; R₁ is—C(O)—C₁₋₂alkyl, —Cl, —Br, —I, C₁₋₃alkyl, or C₃₋₅cycloalkyl; whereinsaid C₁₋₃alkyl may be substituted with halo; R₂ is —F, —Cl, —Br,cyclopropyl, C₁₋₃alkyl, C₁₋₂alkoxy or hydroxyl; wherein said C₁₋₃alkylmay be substituted with halo or hydroxyl; R₃ is —H, halo, or cyano; and

is selected from


3. The compound of claim 2 wherein X is —CH—; R₁ is —C(O)—CH₃, —Cl, —Br,—I, —CF₃, or cyclopropyl; R₂ is —F, —Cl, —Br, cyclopropyl, C₁₋₃alkyl,C₁₋₂alkoxy or hydroxyl; wherein said C₁₋₃alkyl may be substituted withhydroxyl or halo; and R₃ is —H, halo, or cyano.
 4. The compound of claim2 wherein X is —CH—; R₁ is —CF₃, —Br, or —I; R₂ is —CF₃, hydroxyl,—OCH₃, or —Cl; and R₃ is —H, halo, or cyano.
 5. The compound of claim 2wherein X is —CH—; R₁ is —CF₃; R₂ is —CF₃, —OCH₃, or —Cl; and R₃ is —H.6. The compound of claim 2 wherein X is —CH—; R₁ is —CF₃; R₂ is —CF₃ or—Cl; and R₃ is —H.
 7. The compound of claim 1 wherein X is —CH—; R₁ is—C(O)—C₁₋₂alkyl, —Cl, —Br, —I, C₁₋₃alkyl, or C₃₋₅cycloalkyl; whereinsaid C₁₋₃alkyl may be substituted with halo; R₂ is —F, —Cl, —Br,cyclopropyl, C₁₋₃alkyl, C₁₋₂alkoxy or hydroxyl; wherein said C₁₋₃alkylmay be substituted with halo or hydroxyl; R₃ is —H, halo, or cyano; and

is selected from


8. The compound of claim 7 wherein X is —CH—; R₁ is —C(O)—CH₃, —Cl, —Br,—I, —CF₃, or cyclopropyl; R₂ is —F, —Cl, —Br, cyclopropyl, C₁₋₃alkyl,C₁₋₂alkoxy or hydroxyl; wherein said C₁₋₃alkyl may be substituted withhalo or hydroxyl; and R₃ is —H, halo, or cyano.
 9. The compound of claim7 wherein X is —CH—; R₁ is —CF₃, —Br, or —I; R₂ is —CF₃, hydroxyl,—OCH₃, or —Cl; and R₃ is —H, halo, or cyano.
 10. The compound of claim 7wherein X is —CH—; R₁ is —CF₃; R₂ is —CF₃, —OCH₃, or —Cl; and R₃ is —H.11. The compound of claim 7 wherein X is —CH; R₁ is —CF₃; R₂ is —CF₃ or—Cl; and R₃ is —H.
 12. The compound of claim 1 wherein X is —CH—; R₁ is—C(O)—C₁₋₂alkyl, —Cl, —Br, —I, C₁₋₃alkyl, or C₃₋₅cycloalkyl; whereinsaid C₁₋₃alkyl may be substituted with halo; R₂ is —F, —Cl, —Br,cyclopropyl, C₁₋₃alkyl, C₁₋₂alkoxy or hydroxyl; wherein said C₁₋₃alkylmay be substituted with halo or hydroxyl; R₃ is —H, halo, or cyano; and

is selected from


13. The compound of claim 12 wherein X is —CH—; R₁ is —C(O)—CH₃, —Cl,—Br, —I, —CF₃, or cyclopropyl; R₂ is —F, —Cl, —Br, cyclopropyl,C₁₋₃alkyl, C₁₋₂alkoxy or hydroxyl; wherein said C₁₋₃alkyl may besubstituted with halo or hydroxyl; and R₃ is H, halo, or cyano.
 14. Thecompound of claim 12 wherein X is —CH—; R₁ is —CF₃, —Br, or —I; R₂ is—CF₃, hydroxyl, —OCH₃, or —Cl; and R₃ is —H, halo, or cyano.
 15. Thecompound of claim 12 wherein X is —CH—; R₁ is —CF₃; R₂ is —CF₃, —OCH₃,or —Cl; and R₃ is —H.
 16. The compound of claim 12 wherein X is —CH—; R₁is —CF₃; R₂ is —CF₃ or —Cl; and R₃ is —H.
 17. The compound of claim 1selected from1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}piperidine-4-carboxylicacid;5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one;1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carboxylicacid;1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}piperidine-4-carboxylicacid;1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carboxylicacid;2-(3-(S)-Amino-piperidin-1-yl)-5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one;5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[1,4]diazepan-1-yl-thiazol-4-one;5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-methoxy-ethyl)piperazin-1-yl]-thiazol-4-one;2-(3-(R)-Amino-pyrrolidin-1-yl)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one;5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(S)-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-thiazol-4-one;5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-methoxy-ethyl)-piperazin-1-yl]-thiazol-4-one;5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(5-methyl-2S,5S-diaza-bicyclo[2.2.1]hept-2-yl)-thiazol-4-one;5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[5-(2-hydroxy-ethyl)-2S,5S-diaza-bicyclo[2.2.1]hept-2-yl]-thiazol-4-one;2-(4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazin-1-yl)-N,N-dimethyl-acetamide;2-(3-Amino-azetidin-1-yl)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one;5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(8-methyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-thiazol-4-one;5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2-hydroxymethyl-piperazin-1-yl)-thiazol-4-one;5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(1H-tetrazol-5-yl)-piperidin-1-yl]-thiazol-4-one;5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(6-hydroxy-[1,4]diazepan-1-yl)-thiazol-4-one;5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one;5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-((2S)-hydroxymethyl-morpholin-4-yl)-thiazol-4-one;5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3(R)-hydroxymethyl-morpholin-4-yl)-thiazol-4-one;5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3(R)-hydroxymethyl-morpholin-4-yl)-thiazol-4-one;5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-methyl-1H-indazol-5-ylmethylene]-2-(3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one;5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-chloro-1H-indazol-5-ylmethylene]-2(3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one;4-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]morpholine-2-carboxylicacid;1-[5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-1,2,3,6-tetrahydropyridine-4-carboxylicacid; Methyl{1-[5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-5-(R)-(hydroxymethyl)pyrrolidin-3-(R)-yl}carbamate;1-[4-Chloro-2-(trifluoromethyl)benzyl]-5-{[2-(4-methylpiperazin-1-yl)-4-oxo-1,3-thiazol-5(4H)-ylidene]methyl}-1H-indazole-3-carbonitrile;N-{1-[(3R,5R)-5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-5-(hydroxymethyl)pyrrolidin-3-yl}acetamide;and5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-(S)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one.18. The compound of claim 1 selected from1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carboxylicacid;5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one;1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carboxylicacid;1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carboxylicacid;2-(3-(S)-Amino-piperidin-1-yl)-5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one;5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[1,4]diazepan-1-yl-thiazol-4-one;5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-methoxy-ethyl)-piperazin-1-yl]-thiazol-4-one;2-(3-(R)-Amino-pyrrolidin-1-yl)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one;5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(5-methyl-2S,5S-diaza-bicyclo[2.2.1]hept-2-yl)-thiazol-4-one;5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[5-(2-hydroxy-ethyl)-2S,5S-diaza-bicyclo[2.2.1]hept-2-yl]-thiazol-4-one;2-(3-Amino-azetidin-1-yl)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one;5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(6-hydroxy-[1,4]diazepan-1-yl)-thiazol-4-one;5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one;5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-((2S)-hydroxymethyl-morpholin-4-yl)-thiazol-4-one;5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3(R)-hydroxymethyl-morpholin-4-yl)-thiazol-4-one;5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3(R)-hydroxymethyl-morpholin-4-yl)-thiazol-4-one;5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-methyl-1H-indazol-5-ylmethylene]-2-(3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one;5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-chloro-1H-indazol-5-ylmethylene]-2(3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one;4-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]morpholine-2-carboxylicacid;1-[5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-1,2,3,6-tetrahydropyridine-4-carboxylicacid; Methyl{1-[5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-5-(R)-(hydroxymethyl)pyrrolidin-3-(R)-yl}carbamate;1-[4-Chloro-2-(trifluoromethyl)benzyl]-5-{[2-(4-methylpiperazin-1-yl)-4-oxo-1,3-thiazol-5(4H)-ylidene]methyl}-1H-indazole-3-carbonitrile;N-{1-[(3R,5R)-5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-5-(hydroxymethyl)pyrrolidin-3-yl}acetamide;and5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-(S)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one.19. The compound of claim 1 selected from1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carboxylicacid;1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carboxylicacid;2-(3-(S)-Amino-piperidin-1-yl)-5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one;5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[1,4]diazepan-1-yl-thiazol-4-one;2-(3-Amino-azetidin-1-yl)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one;5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(6-hydroxy-[1,4]diazepan-1-yl)-thiazol-4-one;5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one;5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-((2S)-hydroxymethyl-morpholin-4-yl)-thiazol-4-one;5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3(R)-hydroxymethyl-morpholin-4-yl)-thiazol-4-one;5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-methyl-1H-indazol-5-ylmethylene]-2-(3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one;5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-chloro-1H-indazol-5-ylmethylene]-2(3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one;4-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]morpholine-2-carboxylicacid;1-[5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-1,2,3,6-tetrahydropyridine-4-carboxylicacid; Methyl{1-[5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-5-(R)-(hydroxymethyl)pyrrolidin-3-(R)-yl}carbamate;1-[4-Chloro-2-(trifluoromethyl)benzyl]-5-{[2-(4-methylpiperazin-1-yl)-4-oxo-1,3-thiazol-5(4H)-ylidene]methyl}-1H-indazole-3-carbonitrile;and5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-(S)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one.20. The compound of claim 1 selected from


21. A pharmaceutical composition comprising at least one compound ofclaim 1 and at least one pharmaceutically acceptable carrier.
 22. Apharmaceutical composition of claim 21, further comprising at least oneadditional agent, drug, medicament, antibody and/or inhibitor.